Macrocyclic hepatitis C serine protease inhibitors

ABSTRACT

The present invention relates to compounds of Formula I, II or Ill, or a pharmaceutically acceptable salt, ester, or prodrug, thereof:  
                 
wherein W is a substituted or unsubstituted heterocyclic ring system. The compounds inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit to U.S. provisional Ser. No. ______(conversion of U.S. Ser. No. 10/365,854), filed Feb. 13, 2003; ______(conversion of U.S. Ser. No 10/360,947), filed Feb. 7, 2003; ______ and(conversion of U.S. Ser. No. 10/384,120), filed Mar. 7, 2003, each ofwhich is hereby incorporated by reference in its entirety for anypurpose.

TECHNICAL FIELD

The present invention relates to novel macrocycles having activityagainst hepatitis C virus (HCV) and useful in the treatment of HCVinfections. More particularly, the invention relates to macrocycliccompounds, compositions containing such compounds and methods for usingthe same, as well as processes for making such compounds.

BACKGROUND OF THE INVENTION

HCV is the principal cause of non-A, non-B hepatitis and is anincreasingly severe public health problem both in the developed anddeveloping world. It is estimated that the virus infects over 200million people worldwide, surpassing the number of individuals infectedwith the human immunodeficiency virus (HIV) by nearly five fold. HCVinfected patients, due to the high percentage of individuals inflictedwith chronic infections, are at an elevated risk of developing cirrhosisof the liver, subsequent hepatocellular carcinoma and terminal liverdisease. HCV is the most prevalent cause of hepatocellular cancer andcause of patients requiring liver transplantations in the western world.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

Only two approved therapies for HCV infection are currently available.The original treatment regimen generally involves a 3-12 month course ofintravenous interferon-α (IFN-α), while a new approved second-generationtreatment involves co-treatment with IFN-α and the general antiviralnucleoside mimics like ribavirin. Both of these treatments suffer frominterferon-related side effects as well as low efficacy against HCVinfections. There exists a need for the development of effectiveantiviral agents for treatment of HCV infection due to the poortolerability and disappointing efficacy of existing therapies.

In a patient population where the majority of individuals arechronically infected and asymptomatic and the prognoses are unknown, aneffective drug must possess significantly fewer side effects than thecurrently available treatments. The hepatitis C non-structural protein-3(NS3) is a proteolytic enzyme required for processing of the viralpolyprotein and consequently viral replication. Despite the huge numberof viral variants associated with HCV infection, the active site of theNS3 protease remains highly conserved thus making its inhibition anattractive mode of intervention. Recent success in the treatment of HIVwith protease inhibitors supports the concept that the inhibition of NS3is a key target in the battle against HCV.

HCV is a flaviridae type RNA virus. The HCV genome is enveloped andcontains a single strand RNA molecule composed of circa 9600 base pairs.It encodes a polypeptide comprised of approximately 3010 amino acids.

The HCV polyprotein is processed by viral and host peptidase into 10discreet peptides which serve a variety of functions. There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are sixnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease.

The NS3.4A protease is responsible for cleaving four sites on the viralpolyprotein. The NS3-NS4A cleavage is autocatalytic, occurring in cis.The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B alloccur in trans. NS3 is a serine protease which is structurallyclassified as a chymotrypsin-like protease. While the NS serine proteasepossesses proteolytic activity by itself, the HCV protease enzyme is notan efficient enzyme in terms of catalyzing polyprotein cleavage. It hasbeen shown that a central hydrophobic region of the NS4A protein isrequired for this enhancement. The complex formation of the NS3 proteinwith NS4A seems necessary to the processing events, enhancing theproteolytic efficacy at all of the sites.

A general strategy for the development of antiviral agents is toinactivate virally encoded enzymes, including NS3, that are essentialfor the replication of the virus. Current efforts directed toward thediscovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause,Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status andEmerging Strategies, Nature Rev. Drug Discov., 1, 867-881 (2002). Morerelevant patent disclosures describing the synthesis of HCV proteaseinhibitors are: WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543(2000); WO 99/50230 (1999); US5861297 (1999).

SUMMARY OF THE INVENTION

The present invention relates to novel macrocyclic compounds and methodsof treating a hepatitis C infection in a subject in need of such therapywith said macrocyclic compounds. The present invention further relatesto pharmaceutical compositions comprising the compounds of the presentinvention, or pharmaceutically acceptable salts, esters, or prodrugsthereof, in combination with a pharmaceutically acceptable carrier orexcipient.

A compound having the Formula I or a pharmaceutically acceptable salt,ester or prodrug thereof:

wherein:

-   -   A is selected from the group consisting of H, —(C═O)—R²,        —(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R², —S(O)₂—R², —(C═NR¹)—R¹,        and —(C═NR¹)—NH—R¹;    -   G is selected from the group consisting of —OH, —O—(C₁-C₁₂        alkyl), —NHS(O)₂—R¹, —(C═O)—R¹, —(C═O)—R², —(C═O)—O—R¹,        —(C═O)—NH—R¹, and —(C═O)—NH—R²;    -   L is selected from the group consisting of absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,        —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—,        —CF₂CH₂—, and —CR_(x)═CR_(x)— where R_(x)═H or halogen;    -   j is 0, 1, 2, 3, or 4;    -   m is 0, 1,or 2;    -   s is 0, 1 or2;    -   R¹ is selected form the group consisting of H, C₁-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R² is selected from the group consisting of H, C₁-C₆ alkyl,        C₃-C₁₂ cycloalkyl, alkylamino, dialkylamino, arylamino,        diarylamino, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R³ and R⁴ are each independently selected from the group        consisting of hydrogen, OH, CH₃, CN, SH, halogen, NO₂, NH₂,        amide, methoxy, trifluoromethoxy, and trifluoromethyl;    -   E represents either a single bond or a double bond between the        two carbon atoms attached thereto; and    -   W is a substituted or unsubstituted heterocyclic ring system.

In one embodiment of the present invention E represents a double bond,resulting in Formula II or pharmaceutically acceptable salts, esters, orprodrugs thereof:

wherein the remaining substitutents are as described above.

In one embodiment of the present invention E represents a single bond,resulting in Formula II or pharmaceutically acceptable salts, esters, orprodrugs thereof:

wherein the remaining substituents are as described above.

In one embodiment of the present invention there are disclosed compoundsrepresented by Formulas II and II, or pharmaceutically acceptable salts,esters, or prodrugs thereof:

-   -   wherein    -   W is selected from the group consisting of:    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—;    -   Q′ is selected from the group consisting of: absent, —CH₂—, and        —NH—; Y is selected from the group consisting of: H, C₁-C₆        alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   All other substituents are as defined above.

In one embodiment of the present invention there are disclosed compoundsrepresented by Formulas II and III, or pharmaceutically acceptablesalts, esters, or prodrugs thereof wherein

-   -   W is selected from the group consisting of:    -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl;    -   All other substituents are as defined above:

In one embodiment of the present invention there are disclosed compoundsrepresented by Formulas II and III, or pharmaceutically acceptablesalts, esters, or prodrugs thereof wherein:

and

-   -   X, Y, and Z are independently selected from the group consisting        of H, N₃, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, alkylamino,        dialkylamino, C₁-C₆ alkynyl, substituted alkynyl, aryl,        substituted aryl, —S-aryl, —S-substituted aryl, —O-aryl,        —O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino,        diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, —S-heteroaryl, —S-substituted        heteroaryl, —O-heteroaryl, —O-substituted heteroaryl,        —NH-heteroaryl, —NH-substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; or, in the alternative, X and Y or Y and Z        taken together with the carbon atoms to which they are attached        form an aryl, substituted aryl, heteroaryl, or substituted        heteroaryl cyclic moiety.

Other aspects of the invention are:

A compound according to any of the formulae herein wherein W issubstituted with one or more substituents, each of said substituentsbeing independently selected from any of (a), (b), (c), (d) and (e):

-   -   (a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl;        alkylsulfonyl; alkynyl; amide; amido optionally mono-substituted        with C₁-C₆ alkyl; aryl; arylalkanoylalkyl; arylalkyl;        arylaminoalkyl; aryloxyalkyl; arylsulfonyl; cycloalkoxy;        cycloalkyl; dialkylamino; dialkylaminoalkyl; diarylaminoalkyl;        haloalkyl; heteroaryl; heteroarylalkyl; heterocyclo;        heterocycloalkyl; heterocycloalkylalkyl; thioalkyl;        monoalkylaminoalkyl; sulfonyl; (lower alkyl)sulfonyl; haloalkyl;        carboxyl; amide; (lower alkyl)amide; heterocyclo optionally        substituted with C₁-C₆ alkyl; perhaloalkyl; sulfonyl; thioalkyl;        urea, C(═O)—R¹¹; OC(═O)R¹¹; C(═O)O—R¹¹; C(═O)N(R¹¹)₂;        C(═S)N(R¹¹)₂; SO₂R¹¹; NHS(O₂)R¹¹; N(R¹²)₂; N(R¹²)C(═O)R¹¹;        -   wherein each of the foregoing can be optionally be            substituted with up to three groups selected from halogen,            OH, alkoxy, perhaloalkyl;    -   (b) C₇-C₁₄ aralkyl; C₂-C₇cycloalkyl; C₆-C₁₀ aryl; heterocyclo;        (lower alkyl)-heterocyclo;    -   wherein each aralkyl, cycloalkyl, aryl, heterocyclo or (lower        alkyl)-heterocyclo may be optionally substituted with R⁶, where        R⁶ is halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy,        C₃-C₆ cycloalkoxy, NO₂, N(R⁷)₂, NH—C(O)—R⁷ or NH—C(O)—NHR⁷;        where R⁷ is H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl;        -   or R⁶ is NH—C(O)—OR⁸ where R⁸ is C₁-C₆ alkyl or C₃-C₆            cycloalkyl;    -   (c) N(R⁵)₂, NH—C(O)—R⁵, or NH—C(O)—NH—R⁵ where R⁵ is        independently H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, C₆ or C₁₀        aryl, C₇-C₁₄ aralkyl, heterocyclo or (lower alkyl)-heterocyclo;    -   (d) NH—C(O)—OR⁸ where R⁸ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl;    -   (e) formyl; halogen;, hydroxy; NO₂; OH; SH; halo; CN;        -   wherein            -   each R¹¹ is independently H, OH, alkyl, alkenyl,                alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl,                alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl,                arylsulfonyl, heteroaryl, heteroarylalkyl,                arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl,                alkylamino, dialkylamino, monoalkylaminoalkyl,                dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,                wherein any of the foregoing can be optionally be                substituted with up to three groups selected from                halogen, OH, alkoxy and perhaloalkyl; and

each R¹² is independently H, formyl, alkyl, alkenyl, alkynyl,perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo,heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl,heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, ordiarylaminoalkyl, wherein any of the foregoing can be optionally besubstituted with up to three groups selected from halogen, OH, alkoxyand perhaloalkyl;

The compound of any of the formulae herein wherein W is selected fromthe group consisting of:

-   -   (a) an aliphatic heteromonocyclic, heterobicyclic or        heterotricyclic ring system having from five to sixteen ring        atoms and up to four ring hetero atoms selected from O, N and S,        wherein said ring system is optionally substituted with up to        three ring substituents selected from the group consisting of        OH, CN, halogen, formyl, R¹⁰ and R¹¹; and    -   (b) an aromatic heteromonocyclic, heterobicyclic or        heterotricyclic ring system having from five to sixteen ring        atoms and up to four ring hetero atoms selected from O, N and S,        wherein said ring system is optionally substituted with up to        three ring substituents selected from the group consisting of        OH, CN, halogen, formyl, and R¹⁰;    -   wherein:    -   each R¹⁰ is independently alkyl, alkenyl, alkynyl, perhaloalkyl,        alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo,        heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heretoaryl,        heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl        aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl,        dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, heteroaryl        or urea, wherein any of the foregoing can be optionally be        substituted with up to three groups selected from halogen, OH,        alkoxy and perhaloalkyl; C(═O)—R¹¹, OC(═O)R¹¹, C(═O)O—R¹¹,        C(═O)N(R¹¹)₂, C(═S)N(R¹¹)₂, SO₂R¹¹, NHS(O₂)R¹¹, N(R¹¹)₂, and        N(R¹²)C(═O)R¹¹;    -   each R¹¹ is independently H, OH, alkyl, alkenyl, alkynyl,        perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo,        heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl,        heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl        aryloxyalkyl, alkylamino, dialkylamino, monoalkylaminoalkyl,        dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, wherein any        of the foregoing can be optionally be substituted with up to        three groups selected from halogen, OH, alkoxy and perhaloalkyl;    -   each R¹² is independently H, formyl, alkyl, alkenyl, alkynyl,        perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl, heterocyclo,        heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroarylalkyl,        heteroaryl, arylalkanoylalkyl, heterocycloalkylalkyl        aryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,        arylaminoalkyl, or diarylaminoalkyl, wherein any of the        foregoing can be optionally be substituted with up to three        groups selected from halogen, OH, alkoxy and perhaloalkyl;    -   The compound of any of the formulae herein wherein W is an        aliphatic heteromonocyclic, heterobicyclic or heterotricyclic        ring system having from five to sixteen ring atoms and up to        four ring hetero atoms selected from O, N and S, wherein said        ring system is optionally substituted with up to three ring        substituents selected from the group consisting of OH, CN,        halogen, formyl, R₁₀ and R₁₁;    -   The compound of any of the formulae herein wherein W is an        aliphatic heteromonocyclic ring system having from five to seven        ring atoms and up to four ring hetero atoms selected from O, N        and S, wherein said ring system is optionally substituted with        up to three ring substituents selected from the group consisting        of OH, CN, halogen, formyl, R¹⁰ and R¹¹;    -   The compound of any of the formulae wherein said optionally        substituted aliphatic heteromonocyclic ring system has five ring        atoms and 1 or 2 ring hetero atoms selected from O, N and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heteromonocyclic ring system is        selected from the group consisting of pyrrolidines,        pyrazolidines, pyrrolines, tetrahydrothiophenes,        dihydrothiophenes, tetrahydrofurans, dihydrofurans,        imidazolines, tetrahydroimidazoles, dihydropyrazoles,        tetrahydropyrazoles, and oxazolines;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heteromonocyclic ring system        has six ring atoms and 1 or 2 ring hetero atoms selected from O,        N and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heteromonocyclic ring system is        selected from the group consisting of pyridines, piperidines,        dihydropyridines, tetrahydropyridines, dihydropyrans,        tetrahydropyrans, dioxanes, piperazines, dihydropyrimidines,        tetrahydropyrimidines, perhydro pyrimidine, morpholine,        thioxane, and thiomorpholine;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heteromonocyclic ring system        has seven ring atoms and 1 or 2 ring hetero atoms selected from        O, N and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heteromonocyclic ring system is        selected from the group consisting of hexamethyleneimine, and        hexamethylenesulfide;    -   The compound of any of the formulae herein wherein W is an        aliphatic heterobicyclic ring system having from five to sixteen        ring atoms and up to four ring hetero atoms selected from O, N        and S, wherein said ring system is optionally substituted with        up to three ring substituents selected from the group consisting        of OH, CN, halogen, formyl and R₁₀.    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heterobicyclic ring system has        eight to twelve ring atoms and 1 to 4 ring hetero atoms selected        from O, N and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aliphatic heterobicyclic ring system        eight to twelve ring atoms and 1 or 2 ring hetero atoms selected        from O and N;    -   The compound of any of the formulae herein wherein W is an        aromatic heteromonocyclic, heterobicyclic or heterotricyclic        ring system having from five to sixteen ring atoms and up to        four ring hetero atoms selected from O, N and S, wherein said        ring system is optionally substituted with up to three ring        substituents selected from the group consisting of OH, CN,        halogen, formyl and R₁₀;    -   The compound of any of the formulae herein wherein W is an        aromatic heteromonocyclic ring system having from five to seven        ring atoms and up to four ring hetero atoms selected from O, N        and S, wherein said ring system is optionally substituted with        up to three ring substituents selected from the group consisting        of OH, CN, halogen, formyl and R₁₀;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system has        five ring atoms and 1 or 2 ring hetero atoms selected from O, N        and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system is        selected from the group consisting of pyrroles, pyrazoles,        porphyrins, furans, thiophenes, pyrazoles, imidazoles, oxazoles,        oxadiazoles, isoxazoles, thiazoles, thiadiazoles, and        isothiazoles;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system has        six ring atoms and 1, 2 or 3 ring hetero atoms selected from O,        N and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system is        selected from the group consisting of pyridines, pyrimidines,        pyrazines, pyrans, and triazines;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system has        five ring atoms and 3 or 4 ring hetero atoms selected from O, N        and S;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heteromonocyclic ring system is        triazolyl or tetrazolyl;    -   The compound of any of the formulae herein wherein W is an        aromatic heterobicyclic ring system having from eight to twelve        ring atoms and up to four ring hetero atoms selected from O, N        and S, wherein said ring system is optionally substituted with        up to three ring substituents selected from the group consisting        of OH, CN, halogen, formyl and R₁₀;    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heterobicyclic ring system is        selected from the group consisting of adenines,        azabenzimidazoles, azaindoles, benzimidazoles, benzo        isothiazoles, benzofurans, benzoisoxazoles, benzooxazoles,        benzothiadiazoles, benzothiazoles, benzothienes,        benzothiophenes, benzoxazoles, carbazoles, cinnolines, guanines,        imidazopyridines, indazoles, indoles, isoindoles, isoquinolines,        phthalazines, purines, pyrrolo pyridines, quinazolines,        quinolines, quinoxalines, thianaphthenes, and xanthines;    -   The compound of any of the formulae herein wherein W is an        aromatic heterotricyclic ring system having from ten to sixteen        ring atoms and up to four ring hetero atoms selected from O, N        and S, wherein said ring system is optionally substituted with        up to three ring substituents selected from the group consisting        of OH, CN, halogen, formyl, R₁₀ and R₁₁; and    -   The compound of any of the formulae herein wherein said        optionally substituted aromatic heterotricyclic ring system is        selected from the group consisting of carbazoles, bibenzofurans,        psoralens, dibenzothiophenes, phenazines, thianthrenes,        phenanthrolines, phenanthridines.

Other embodiments are a compound of Formula II

Wherein:

-   -   A is selected from the group consisting of H, —(C═O)—R²,        —(C═O)—O—R^(I), —C(═O)—NH—R¹, —C(═S)—NH—R² , —S(O)₂—R²,        —(C═NR¹)—R¹, and —(C═NR¹)—NH—R¹;    -   G is selected from the group consisting of —OH, —O—(C₁-C₁₂        alkyl), —NHS(O)₂—R^(I), —(C═O)—R², —(C═O)—O—R^(I), and        —(C═O)—NH—R²;    -   L is selected from the group consisting of absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂, —O—,        —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—,        —CF₂CH₂—, and —CR_(x)═CR_(x)— where R_(x)═H or halogen;    -   W is selected from the group consisting of    -   Q is selected from the group consisting of absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—;    -   Q′ is selected from the group consisting of absent, —CH₂—, and        —NH—;    -   Y is selected from the group consisting of H, C_(I)-C₆ alkyl,        aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyu, and substituted        heterocycloalkyl;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0,1 or 2;    -   R¹ is selected from the group consisting of H, C_(I)l-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R² is selected from the group consisting of H, C₁-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, alkylamino,        dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; and    -   R³ and R⁴ are each independently selected from the group        consisting of hydrogen and methyl;

A compound of the above formula II, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound of theabove formula II, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound of theabove formula II, wherein:

-   -   A is —(C═O)—O—R¹,    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen; and

A compound of theabove formula II, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen.

Other embodiments are:

A compound of Formula III:

wherein

-   -   A is selected from the group consisting of H, —(C═O)—R²,        —(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R² , —S(O)₂—R²,        —(C═NR¹)—R¹, and —(C═NR¹)—NH—R¹;    -   G is selected from the group consisting of —OH, —O—(C₁-C₁₂        alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R^(I), and        —(C═O)—NH—R²;    -   L is selected from the group consisting of absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,        —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—,        —CF₂CH₂—, and —CR_(x)═CR_(x)— where R_(x)═H or halogen;    -   W is selected from the group consisting of    -   Q is selected from the group consisting of absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—;    -   Q′ is selected from the group consisting of absent, —CH₂—, and        —NH—;    -   Y is selected from the group consisting of H, C_(I)-C₆ alkyl,        aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0, 1 or 2;    -   R¹ is selected from the group consisting of H, C_(I)-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R² is selected from the group consisting of H, C_(I)-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, alkylamino,        dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; and    -   R³ and R⁴ are each independently selected from the group        consisting of hydrogen and methyl;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound of Formula II:

wherein

-   -   A is selected from the group consisting of H, —(C═O)—R²,        —(C═O)—O—R^(I), —C(═O)—NH—R², —C(═S)—NH—R² , —S(O)₂—R²,        —(C═NR¹)—R¹, and —(C═NR¹)—NH—R¹;    -   G is selected from the group consisting of —OH, —O—(C₁-C₁₂        alkyl), —NHS(O)₂—R^(I), —(C═O)—R², —(C═O)—O—R^(I), and        —(C═O)—NH—R²;    -   L is selected from the group consisting of absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,        —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—,        —CF₂CH₂—, and —CR_(x)═CR_(x)— where R_(x)═H or halogen;    -   W is selected from the group consisting of    -   where X and Y are independently selected from the group        consisting of H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,        —CH₂-alkylamino, —CH₂-dialkylamino, —CH₂-arylamino,        —CH₂-diarylamino, —(C═O)-alkylamino, —(C═O)-dialkylamino,        —(C═O)-arylamino, —(C═O)-diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; in the        alternative, X and Y taken together with the carbon atoms        occupying the 4 and 5 positions of the triazole ring, to which X        and Y are attached, for a cyclic moiety selected from the group        consisting of aryl, substituted aryl, heteroaryl, and        substituted heteroaryl;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0, 1 or 2;    -   R¹ is selected from the group consisting of H, C_(I)-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R² is selected from the group consisting of H, C_(I)-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, alkylamino,        dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; and    -   R³ and R⁴ are each independently selected from the group        consisting of hydrogen and methyl;

A compound according to formula II above, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula II above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³and R⁴are hydrogen;

A compound according to formula II above, wherein:

-   -   A is —(C═O)—O—R¹,    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula II above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   W is    -   J=3;    -   M=s=1; and    -   R³ and R⁴ are hydrogen.

Other embodiments are a compound of Formula III:

wherein

-   -   A is selected from the group consisting of H, —(C═O)—R²,        —(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R², —S(O)₂—R², —(C═NR¹)—R¹,        and —(C═NR¹)—NH—R¹;    -   G is selected from the group consisting of —OH, —O—(C₁-C₁₂        alkyl), —NHS(O)₂—R^(I), —(C═O)—R², —(C═O)—O—R^(I), and        —(C═O)—NH—R²;    -   L is selected from the group consisting of absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—,        —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and        —CR_(x)═CR_(x)— where R_(x)═H or halogen;

from the group consisting of

-   -   where X and Y are independently selected from the group        consisting of H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,        —CH₂-alkylamino, —CH₂-dialkylamino, —CH₂-arylamino,        —CH₂-diarylamino, —(C═O)-alkylamino, —(C═O)-dialkylamino,        —(C═O)-arylamino, —(C═O)-diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; in the        alternative, X and Y taken together with the carbon atoms        occupying the 4 and 5 positions of the triazole ring, to which X        and Y are attached, for a cyclic moiety selected from the group        consisting of aryl, substituted aryl, heteroaryl, and        substituted heteroaryl;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0, 1 or2;    -   R¹ is selected from the group consisting of H, C₁-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl;    -   R² is selected from the group consisting of H, C_(I)-C₆ alkyl,        C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, alkylamino,        dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; and    -   R³ and R⁴ are each independently selected from the group        consisting of hydrogen and methyl;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O—R^(I);    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O—R^(I),    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=I; and    -   R³ and R⁴ are hydrogen;

A compound according to formula III above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   W is    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound of Formula IV:

wherein

-   -   A is hydrogen, —(C═O)—R¹, —(C═O)—O—R¹, —C(═O)—NH—R²,        —C(═S)—NH—R², —S(O)₂—R², —(C═NR¹)—R¹, or —(C═NR¹)—NH—R¹;    -   G is —OH, —O—(C₁-C₁₂ alkyl), —NHS(O)₂—R^(I), —(C═O)—R²,        —(C═O)—O—R^(I), or —(C═O)—NH—R²;    -   L is —S—, —SCH₂—, —SCH₂CH₂—, —S(O)²—, —S(O)²CH²CH²—, —S(O)—,        —S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—,        —CFHCH₂— —CF₂CH₂—, or —CR_(x)═CR_(x)— where R_(x)═H or halogen;    -   X, Y, and Z are independently selected from the group consisting        of hydrogen, N₃, halogen, C_(I)-C₆ alkyl, C₃-C₁₂ cycloalkyl,        alkylamino, dialkylamino, C_(I)-C₆ alkynyl, substituted alkynyl,        aryl, substituted aryl, —S-aryl, —S-substituted aryl, —O-aryl,        —O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino,        diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, —S-heteroaryl, —S-substituted        heteroaryl, —O-heteroaryl, —O-substituted heteroaryl,        —NH-heteroaryl, —NH-substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; or,    -   in the alternative, X and Y or Y and Z taken together with the        carbon atoms to which they are attached form an aryl,        substituted aryl, heteroaryl, or substituted heteroaryl cyclic        moiety;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0, 1 or2;    -   R¹ is hydrogen, C_(I)-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted        C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        or substituted heterocycloalkyl;    -   R² is hydrogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted        C₃-C₁₂ cycloalkyl, alkylamino, dialkyl amino, arylamino,        diarylamino, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, or substituted        heterocycloalkyl; and    -   R³ and R⁴ are each independently hydrogen or methyl;

A compound according to formula IV above, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound according to formula IV above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen;

A compound of Formula V:

wherein

-   -   A is hydrogen, —(C═O)—R¹, —(C═O)—O—R^(I), —C(═O)—NH—R²,        —C(═S)—NH—R², or —S(O)₂—R², —(C═NR¹)—R¹, or —(C═NR¹)—NH—R¹;    -   G is —OH, —O—(C₁-C₁₂ alkyl), —NHS(O)₂—R^(I), —(C═O)—R²,        —(C═O)—O—R^(I), or —(C═O)—NH—R²;    -   L is absent, —S—, —SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—,        —S(O)—, —S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—,        —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, or —CR_(x)═CR_(x)— where        R_(x)═H or halogen-;    -   X, Y, and Z are independently selected from the group consisting        of hydrogen, N₃, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,        alkylamino, dialkylamino, C₁-C₆ alkynyl, substituted alkynyl,        aryl, substituted aryl, —S-aryl, —S-substituted aryl, —O-aryl,        —O-substituted aryl, NH-aryl, NH-substituted aryl, diarylamino,        diheteroarylamino, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, —S-heteroaryl, —S-substituted        heteroaryl,    -   —O-heteroaryl, —O-substituted heteroaryl, —NH-heteroaryl,        —NH-substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; or,    -   in the alternative, X and Y or Y and Z taken together with the        carbon atoms to which they are attached form an aryl,        substituted aryl, heteroaryl, and substituted heteroaryl cyclic        moiety;    -   j=0, 1, 2, 3, or 4;    -   m=0, 1, or 2;    -   s=0, 1 or2;    -   R¹ is hydrogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted        C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        or substituted heterocycloalkyl;    -   R² is hydrogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted        C₃-C₁₂ cycloalkyl, alkylamino, dialkyl amino, arylamino,        diarylamino, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, or substituted        heterocycloalkyl; and    -   R³ and R⁴ are each independently hydrogen or methyl;

A compound according to formula V above, wherein:

-   -   A is —(C═O)—O—R¹;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen; and

A compound according to formula V above, wherein:

-   -   A is —(C═O)—O-tert-butyl;    -   G is hydroxyl;    -   L is absent;    -   j=3;    -   m=s=1; and    -   R³ and R⁴ are hydrogen.

Other embodiments are:

-   -   compounds of formulae II or III as delineated herein, wherein:    -   A is selected from the group consisting of: H, —(C═O)—R²,        —(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R², and —S(O)₂—R²; G is        selected from the group consisting of: —OH, —O—(C₁-C₁₂ alkyl),        —NHS(O)₂—R¹, —(C═O)—R¹, —(C═O)—O—R¹, and —(C═O)—NH—R¹; L is        selected from the group consisting of: absent, —S—, —SCH₂—,        —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,        —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, and        —CF₂CH₂—; W is selected from the group consisting of:    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=0, 1, 2,        3, or 4; m=0, 1, or 2; s=0, 1 or 2; R¹ is selected from the        group consisting of: H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,        substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; R² is        selected from the group consisting of: H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino,        aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; and R³ and R⁴ are each independently selected        from the group consisting of hydrogen and methyl;    -   compounds of formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of formula II wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—;    -   Q′ is selected from the group consisting of: absent, —CH₂—, and        —NH—; Y is selected from the group consisting of: H, C₁-C₆        alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; j=3; m=s=1; and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula III, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹), —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from the        group consisting of: absent, —CH₂—, and —NH—; Y is selected from        the group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen; and    -   Compounds of Formula II, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen.

Other embodiments are:

-   -   Compounds of formulae II or III wherein wherein A is selected        from the group consisting of: H, —(C═O)—R², —(C═O)—O—R¹,        —C(═O)—NH—R², —C(═S)—NH—R², and —S(O)₂—R²; G is selected from        the group consisting of: —OH, —O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹,        —(C═O)—R², —(C═O)—O—R¹, and —(C═O)—NH—R²; L is selected from the        group consisting of: absent, —S—, —SCH₂—, —SCH₂CH₂—, —S(O)₂—,        —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—,        —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂— and —CF₂CH₂—; W is selected        from the group consisting of:    -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=0,        1, 2, 3, or 4; m=0, 1, or 2; s=0, 1, or 2; R¹ is selected from        the group consisting of: H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,        substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; R² is        selected from the group consisting of: H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino,        aryl, substituted aryl, arylalkyl, substituted arylalkyl,        heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted        heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; and R³ and R⁴ are each independently selected        from the group consisting of hydrogen and methyl;

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is selected from thegroup consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂—arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is selected from the group consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula III, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is selected from thegroup consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula III, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is selected from the group consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        C═O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; in the alternative, X and Y taken together        with the carbon atoms occupying the 4 and 5 positions of the        triazole ring, to which X and Y are attached, form a cyclic        moiety selected from the group consisting of aryl, substituted        aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R³        and R⁴ are hydrogen;

A compound of Formula III, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen; and

A compound of Formula III, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen.

Other embodiments are compounds of formulae IV or V:

wherein A is H, —(C═O)—R², —(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R², or—S(O)₂—R²; G is —OH, —O—(C—hd-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R²,—(C═O)—O—R¹, or —(C═O)—NH—R²; L is absent, —S—, —SCH₂—, —SCH₂CH₂—,—S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—,—(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂— or —CF₂CH₂—; X, Y, and Z areindependently selected from the group consisting of H, N₃, halogen,C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, alkylamino, dialkylamino, C₁-C₆ alkynyl,substituted alkynyl, aryl, substituted aryl, —S-aryl, —S-substitutedaryl, —O-aryl, —O-substituted aryl, NH-aryl, NH-substituted aryl,diarylamino, diheteroarylamino, arylalkyl, substituted arylalkyl,heteroaryl, substituted heteroaryl, —S-heteroaryl, —S-substitutedheteroaryl, —O-heteroaryl, —O-substituted heteroaryl, —NH-heteroaryl,—NH-substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, heterocycloalkyl, and substituted heterocycloalkyl; or,in the alternative, X and Y or Y and Z taken together with the carbonatoms to which they are attached form an aryl, substituted aryl,heteroaryl, or substituted heteroaryl cyclic moiety; j =0, 1, 2, 3, or4; m=0, 1, or 2; s=0, 1, or 2; R¹ is H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkylsubstituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl; R² is H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl,alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, or substituted heterocycloalkyl; and R³ and R⁴ areeach independently hydrogen or methyl;

A compound of Formula IV, wherein A is —(C═O)—O—R¹; G is hydroxyl; L isabsent; ; j=3; m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula IV, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula V, wherein A is —(C═O)—O—R¹; L is absent; j=3;m=s=1; and R³ and R⁴ are hydrogen; and

A compound of Formula V, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.

Another aspect is a compound of formula I, wherein W is

wherein V, X, Y, and Z are each independently selected from:

-   -   a) —C₁-C₆ alkyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   b) —C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   c) —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   d) aryl;    -   e) substituted aryl;    -   f) heteroaryl;    -   g) substituted heteroaryl;    -   h) heterocycloalkyl; or    -   i) substituted heterocycloalkyl;        or in the alternative, V and X, X and Y, or Y and Z are taken        together with the carbons to which they are attached to for a        cyclic moiety selected from: aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocycloalkyl, or substituted        heterocycloalkyl;

Another aspect is a compound of formula I, wherein W is

wherein X, Y, and Z are each independently selected from:

-   -   a) —C₁-C₆ alkyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   b) —C₂-C₆ alkenyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   c) —C₂-C₆ alkynyl containing 0, 1, 2, or 3 heteroatoms selected        from O, S, or N, optionally substituted with one or more        substituent selected from halogen, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, heterocycloalkyl, or        substituted heterocycloalkyl;    -   d) aryl;    -   e) substituted aryl;    -   f) heteroaryl;    -   g) substituted heteroaryl;    -   h) heterocycloalkyl; or    -   i) substituted heterocycloalkyl;        or in the alternative, Y and Z are taken together with the        carbons to which they are attached to for a cyclic moiety        selected from: aryl, substituted aryl, heteroaryl, substituted        heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;

All remaining substituents are as listed above.

Another aspect is a method for making a compound of Formula I herein,comprising the steps of: (i) reacting a proline derivative of formulaVI:

wherein,

-   -   P is a nitrogen-protecting group (e.g., BOC);    -   L is a leaving group (e.g., halide, OMs);    -   R is optionally substituted alkyl, optionally substituted        aralkyl, or optionally substituted heteroaralkyl;        with a nucleophilic heterocyclic compound; and (ii) converting        the resulting compound to a compound of Formula I as delineated        herein.

Another aspect is a method for making a compound of Formula I herein,comprising the steps of: (i) reacting a compound of formula VII:

wherein,

-   -   L is a leaving group (e.g., halide, OMs);    -   A is a nitrogen protecting group (e.g., BOC); and    -   the remaining variables are as defined for formula I;        with a nucleophilic heterocyclic compound; and (ii) converting        the resulting compound to a compound of Formula I as delineated        herein.

In other aspects, the invention relates to a method for making acompound of any of the formulae delineated herein (e.g., Formulae I toVII with substituent variables as defined anywhere herein) or apharmaceutically acceptable salt, ester or prodrug thereof, comprisingthe steps of: (i) reacting a proline derivative described herein(including that having a mesylate substituent) with a nucleophilic form(e.g., protonated or corresponding metal salt form) of a heterocycliccompound; and (ii) converting the resulting compound to a compound ofany of the formulae delineated herein. In other aspects the methodincludes reacting any one or more intermediate compounds as describedherein, or includes any one or more steps or reagents or combination oftransformations as specifically delineated in the examples and schemesherein.

In another aspect, the invention relates to a method of making apharmceutical composition comprising combining a compound of any of theformulae herein or a pharmaceutically acceptable salt, ester or prodrugthereof, with a pharmaceutically acceptable carrier.

Another aspect is a compound of formulae VI or VII wherein L is OMs andA and the remaining variables are as defined for any of the formulae(e.g., I, II, III) herein.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by FormulaI as described above, or a pharmaceutically acceptable salt, ester orprodrug thereof, in combination with a pharmaceutically acceptablecarrier or excipient.

In some embodiments, the compounds may be of any of the formulaedelineated herein (including any substituent variables as definedanywhere delineated herein) wherein W is selected from the followingaromatics, which may optionally be substituted:

In other embodiments, the compounds may be of any of the formulaedelineated herein (including any substituent variables as definedanywhere delineated herein) wherein W is selected from the followingnon-aromatics, which may be optionally substituted:

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula II asdescribed above where W is a tetrazole or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula III asdescribed above wherein W is a tetrazole, or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Exemplary tetrazolyl macrocyclic compounds and associated methods of theinvention are disclosed in U.S. Provisional Patent application No.______ (conversion of U.S. Ser. No. 10/365,854), filed Feb. 13, 2003.Representative subgenera of the invention include, but are not limitedto:

-   -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹), —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from the        group consisting of: absent, —CH₂—, and —NH—; Y is selected from        the group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula II, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from        the group consisting of: absent, —CH₂—, and —NH—; Y is selected        from the group consisting of: H, C₁-C₆ alkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen;    -   Compounds of Formula III, wherein A is ‘(C═O)—O—R¹, R¹ is        selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂        cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted        aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen; and    -   Compounds of Formula III, wherein A is —(C═O)—O-tert-butyl; G is        hydroxyl; L is absent; W is    -   Q is selected from the group consisting of: absent, —CH₂—, —O—,        —NH—, —N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Y is selected from the        group consisting of: H, C₁-C₆ alkyl, aryl, substituted aryl,        arylalkyl, substituted arylalkyl, heteroaryl, substituted        heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,        heterocycloalkyl, and substituted heterocycloalkyl; j=3; m=s=1;        and R³ and R⁴ are hydrogen.

Representative compounds of the invention include, but are not limitedto, the following compounds: TABLE 1 A G L W Q Y J R³, R⁴ Compounds ofFormula II, where m = S = 1 tBOC OH Absent

Absent phenyl 3 R³ = R⁴ = H; tBOC OH Absent

Absent 2-bromophenyl 3 R³ = R⁴ = H; tBOC OH Absent

Absent 3-bromophenyl 3 R³ = R⁴ = H; tBOC OH Absent

Absent 4-bromophenyl 3 R³ = R⁴ = H; tBOC OH Absent

Absent 5-Bromo-2-thienyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 2-bromo-4-pyridyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 2-biphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-biphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-biphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-(3-thienyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-(p-trifluoromethoxyphenyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-(p-cyanophenyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-(3-thienyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

absent 4-(p-trifluoromethoxyphenyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-(p-cyanophenyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 5-phenyl-2-thienyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 5-phenyl-3-pyridyl 3 R³ = R⁴ = H; TBOC OEt Absent

Absent 3-chloro-4-hydroxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-hydroxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-bromo-4-hydroxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 2-methyl-4-bromophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-methyl-4-bromophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent n-propyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent n-butyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-ethoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-propoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-butoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-methoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3,4-dimethoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-methoxy-1-naphthyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-phenoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent benzyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent p-phenylbenzyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chlorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-fluorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-methoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-phenoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-benzyloxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-trifluoromethylphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-bromophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-fluorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-methoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-ethoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-trifluoromethylphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 5-di(trifluoromethyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl 3 R³ = R⁴ =H; TBOC OH Absent

Absent 2,4-dichlorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3,5-dichlorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3,4-dichlorophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 2-pyridyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 2-pyridyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-pyridyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-pyridyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-methoxy-3-bromophenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 4-(methylcyclopropane)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-(methylcyclopropane)phenyl 3 R³ = R⁴ = H; TBOC OHAbsent

Absent 3-chloro-4-methoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-ethoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-bromo-4-ethoxyphenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-(2-hydroxyethoxy)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-bromo-4-(2-hydroxyethoxy)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-(O-allyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-bromo-4-(O-allyl)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-(O—CH₂SCH₃)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Absent 3-chloro-4-(O—CH₂SCH₃)phenyl 3 R³ = R⁴ = H; TBOC OH Absent

Q′ = —CH₂—

3 R³ = R⁴ = H; TBOC OH Absent

Q′ = —CH₂—

3 R³ = R⁴ = H; —(C═O)—O—R¹ wherein R¹ = cyclopentyl OH Absent

Absent phenyl 3 R³ = R⁴ = H; —(C═O)—O—R¹ wherein R¹ = cyclobutyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H; —(C═O)—O—R¹ wherein R¹ = cyclohexyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H;

OH Absent

Absent phenyl 3 R³ = R⁴ = H;

OH Absent

Absent phenyl 3 R³ = R⁴ = H;

OH Absent

Absent phenyl 3 R³ = R⁴ = H; —(C═O)—R¹ wherein R¹ = cyclopentyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H; —(C═O)—NH—R¹ wherein R¹ = cyclopentyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H; —(C═S)—NH—R¹ wherein R¹ = cyclopentyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H; —S(O)₂—R¹ wherein R¹ = cyclopentyl OHAbsent

Absent phenyl 3 R³ = R⁴ = H; tBOC —O—CH₂-cyclopentyl Absent

Absent phenyl 3 R3 = R4 = H; tBOC —NHC(O)₂—CH₂-cyclopentyl Absent

Absent phenyl 3 R³ = R⁴ = H; tBOC —(C═O)—CH₂-cyclopentyl Absent

Absent Phenyl 3 R³ = R⁴ = H; tBOC —(C═O)—O—CH₂-cyclopentyl Absent

Absent phenyl 3 R³ = R⁴ = H; tBOC —(C═O)—OH Absent

Absent phenyl 3 R³ = R⁴ = H; tBOC —(C═O)—NH—CH₂-cyclopentyl Absent

Absent phenyl 3 R³ = R⁴ = H; tBOC OH —(C═O)CH₂—

Absent phenyl 1 R³ = R⁴ = H; tBOC OH —CH(CH₃)CH₂—

Absent phenyl 1 R³ = methyl, R⁴ = H; tBOC OH —O—

Absent phenyl 0 R³ = methyl R⁴ = H; tBOC OH —S—

Absent phenyl 0 R³ = methyl, R⁴ = H; tBOC OH —S(O)—

Absent phenyl 0 R³ = methyl, R⁴ = H; tBOC OH —S(O)₂—

Absent phenyl 0 R³ = methyl, R⁴ = H; tBOC OH —SCH₂CH₂—

Absent phenyl 0 R³ = R⁴ = CH₃; tBOC OH —CF₂CH₂—

Absent phenyl 1 R³ = R⁴ = H; tBOC OH —CFHCH₂—

Absent phenyl 1 R³ = R⁴ = H; Compounds of Formula III, where m = s = 1tBOC OH Absent

Absent phenyl 3 R³ = R⁴ = H.

The following additional tetrazolyl macrocyclic molecules of theinvention were made by the methods and procedures described herein.While stereochemistry is shown, the invention is not limited to thestereochemistry depicted. Those of ordinary skill in the art willreadily appreciate that other isomers of these compounds are also withinthe scope of the invention.

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula II asdescribed above where W is a triazole or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula III asdescribed above where W is a triazole or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Exemplary triazole macrocyclic compounds and associated methods of theinvention are disclosed in U.S. Provisional Patent application No.______ (conversion of U.S. Ser. No. 10/360,947), filed Feb. 7, 2003.Representative subgenera of the invention include, but are not limitedto:

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is selected from thegroup consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is selected from the group consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        C═O)-diarylamino, aryl, substituted aryl, arylalkyl, substituted        arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,        substituted heteroarylalkyl, heterocycloalkyl, and substituted        heterocycloalkyl; in the alternative, X and Y taken together        with the carbon atoms occupying the 4 and 5 positions of the        triazole ring, to which X and Y are attached, form a cyclic        moiety selected from the group consisting of aryl, substituted        aryl, heteroaryl, and substituted heteroaryl; j=3; m=s=1; and R³        and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W is selected from thegroup consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula III, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is selected from the group consisting of:

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O—R¹, R¹ is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; G is hydroxyl; L is absent; W

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen; and

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W

-   -   X and Y are independently selected from the group consisting of:        H, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,        —CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino,        —(C═O)-alkylamino, —(C═O)-dialkylamino, —(C═O)-arylamino,        —(C═O)-diarylamino, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl,        and substituted heterocycloalkyl; in the alternative, X and Y        taken together with the carbon atoms occupying the 4 and 5        positions of the triazole ring, to which X and Y are attached,        form a cyclic moiety selected from the group consisting of aryl,        substituted aryl, heteroaryl, and substituted heteroaryl; j=3;        m=s=1; and R³ and R⁴ are hydrogen.

Representative compounds of the invention include, but are not limitedto, the following compounds: TABLE 2 Compounds of Formula II where m = s= 1 A G L W j R³,R⁴ tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H. tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent Benzotriazole 3 R³ = R⁴ = H; tBOC OHabsent 5,6-methylbenzotriazole 3 R³ = R⁴ = H; and tBOC OH absent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl OH absent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclobutyl OH absent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclohexyl OH absent

3 R³ = R⁴ = H;

OH absent

3 R³ = R⁴ = H;

OH absent

3 R³ = R⁴ = H;

OH absent

3 R³ = R⁴ = H; —(C═O)—R²; wherein R² = cyclopentyl OH absent

3 R³ = R⁴ = H; —(C═O)—NH—R²; wherein R² = cyclopentyl OH absent

3 R³ = R⁴ = H; wherein R² = cyclopentyl OH absent

3 R³ = R⁴ = H; —S(O)₂—R²; wherein R² = cyclopentyl OH absent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl —O-phenethyl absent

3 R3 = R4 = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl —NH-phenethylabsent

3 R3 = R4 = H; —(C═O)—O—R¹ wherein R¹ = cyclopentyl —NHS(O)₂-phenethylabsent

3 R3 = R4 = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl —(C═O)—OH absent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl —(C═O)—O-phenethylabsent

3 R³ = R⁴ = H; —(C═O)—O—R¹; wherein R¹ = cyclopentyl —(C═O)—NH-phenethylabsent

3 R³ = R⁴ = H; —(C═O)—O—R¹ wherein R¹ = cyclopentyl —(C═O)—NH—S(O)₂-ben-zyl absent

3 R³ = R⁴ = H; tBOC OH —(C═O)CH₂—

1 R³ = R⁴ = H; tBOC OH —CH(CH₃)CH₂—

1 R³ =methyl R⁴ = H tBOC OH —O—

0 R³ =methyl; R⁴ = H; tBOC OH —S—

0 R³ =methyl; R⁴ = H; tBOC OH —S(O)—

0 R³ =methyl; R⁴ = H; tBOC OH —S(O)₂—

0 R³ =methyl; R⁴ = H; tBOC OH —SCH₂CH₂—

0 R³ = R⁴ = CH₃; tBOC OH —CF₂CH₂—

1 R³ = R⁴ = H; tBOC OH —CFHCH₂—

1 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H; tBOC OH absent

3 R³ = R⁴ = H.

The following additional triazole macrocyclic molecules of the inventionwere made by the methods and procedures described herein. Whilestereochemistry is shown, the invention is not limited to thestereochemistry depicted. Those of ordinary skill in the art willreadily appreciate that other isomers of these compounds are also withinthe scope of the invention.

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula II asdescribed above where W is a pyridazinone or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Another embodiment of the invention is a compound, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, represented by Formula III asdescribed above where W is a pyridazinone or derivative thereof, incombination with a pharmaceutically acceptable carrier or excipient.

Exemplary pyridazinone macrocyclic compounds and associated methods ofthe invention are disclosed in U.S. Provisional Patent application No.______ (conversion of U.S. Ser. No. 10/384,120), filed Mar. 7, 2003.Representative subgenera of the invention include, but are not limitedto:

A compound of Formula II, wherein A is —(C═O)—O—R¹; G is hydroxyl; L isabsent; j=3; m=s=1; W=

and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; j=3; m=s=1; W=

and R³ and R⁴ are hydrogen;

A compound of Formula II, wherein A is —(C═O)—O—R¹; L is absent; j=3;m=s=1; W=

and R³ and R⁴ are hydrogen; and

A compound of Formula III, wherein A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; j=3; m=s=1; W=

and R³ and R⁴ are hydrogen.

Representative compounds of the invention include, but are not limitedto, the following compounds: TABLE 3

A G L X, Y Z j R³, R⁴ TBOC OEt absent X = Y = bromo Z = hydrogen 3 R³ =R⁴ = hydrogen; TBOC OEt absent X = Y = thiophen-3-yl Z = hydrogen 3 R³ =R⁴ = hydrogen; TBOC OH absent X = Y = thiophen-3-yl Z = hydrogen 3 R³ =R⁴ = hydrogen; TBOC OH absent X = Y = phenyl Z = hydrogen 3 R³ = R⁴ =hydrogen; TBOC OH absent X = Y = 4-(N,N-dimethyl- Z = hydrogen 3 R³ = R⁴= amino)phenyl hydrogen; TBOC OH absent X = Y = 4-(trifluoro- Z =hydrogen 3 R³ = R⁴ = methoxy)phenyl hydrogen; TBOC OH absent X = Y =4-(methane- Z = hydrogen 3 R³ = R⁴ = sulfonyl)phenyl hydrogen; TBOC OHabsent X = Y = 4-(cyano)phenyl Z = hydrogen 3 R³ = R⁴ = hydrogen; TBOCOH absent X = Y = 3-pyridyl Z = hydrogen 3 R³ = R⁴ = hydrogen; TBOC OHabsent X = Y = 4-(morpho- Z = hydrogen 3 R³ = R⁴ = lin-4-yl-meth-hydrogen; anonyl)phenyl TBOC OH absent X = Y = bromo Z = hydrogen 3 R³ =R⁴ = hydrogen; TBOC OH absent X and Y taken together = phenyl Z =4-meth- 3 R³ = R⁴ = oxy-phenyl hydrogen; TBOC OH absent X and Y takentogether = phenyl Z = 4-chloro- 3 R³ = R⁴ = phenyl hydrogen; TBOC OHabsent X = 4-fluorophenyl Z = phenyl 3 R³ = R⁴ = Y = hydrogen hydrogen;TBOC OH absent X = hydrogen Z = phenyl 3 R³ = R⁴ = Y = 1-piperidylhydrogen; TBOC OEt absent X = hydrogen Z = phenyl 3 R³ = R⁴ = Y = bromohydrogen; TBOC OH absent X = hydrogen Z = phenyl 3 R³ = R⁴ = Y =thiophen-3-yl hydrogen; TBOC OEt absent X = bromo Z = hydrogen 3 R³ = R⁴= Y = pyrrolid-1-yl hydrogen; TBOC OH absent X = thiophen-3-yl Z =hydrogen 3 R³ = R⁴ = Y = pyrrolid-1-yl hydrogen; TBOC OEt absent X =bromo Z = hydrogen 3 R³ = R⁴ = Y = azido hydrogen; TBOC OEt absent X =thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = Y = azido hydrogen; TBOC OHabsent X = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = Y = azido hydrogen;TBOC OH absent X = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = Y =tetrazol-2-yl hydrogen; TBOC OH absent X = Y = mercapto-2-pyrimidine Z =hydrogen 3 R³ = R⁴ = hydrogen; TBOC OH absent X = bromo Z = hydrogen 3R³ = R⁴ = Y = mercapto-2-pyrimidine hydrogen; TBOC OH absent X =thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = Y = mercapto-2-pyrimidinehydrogen; TBOC OH absent X = Y = thiazol-2-yl Z = hydrogen 3 R³ = R⁴ =hydrogen; TBOC OH absent X = Y = imidazol-1-yl Z = hydrogen 3 R³ = R⁴ =hydrogen; TBOC OH absent X = 2-(cyclo- Z = hydrogen 3 R³ = R⁴ =propylamino)-thiazol-4-yl hydrogen; Y = 4-methoxyphenyl TBOC OH absent Xand Y taken Z = hydrogen 3 R³ = R⁴ = together = 6-meth- hydrogen;oxy-isoquinolinyl —(C═O)—O—R¹ OH absent X = Y = thiophen-3-yl Z =hydrogen 3 R³ = R⁴ = Wherein hydrogen; R¹ = cyclopentyl —(C═O)—O—R¹ OHabsent X = Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = wherein R¹ =hydrogen; cyclobutyl —(C═O)—O—R¹ OH absent X = Y = thiophen-3-yl Z =hydrogen 3 R³ = R⁴ = wherein R¹ = hydrogen; cyclohexyl

OH absent X = Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ =hydrogen;

OH absent X = Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ =hydrogen;

OH absent X = Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ =hydrogen; TBOCOH —(C═O)CH₂— X = Y = thiophen-3-yl Z = hydrogen 1 R³ = R⁴ = hydrogen;TBOC OH —CH(CH₃)CH₂— X = Y = thiophen-3-yl Z = hydrogen 1 R³ = methyl R⁴= hydrogen TBOC OH —O— X = Y = thiophen-3-yl Z = hydrogen 0 R³ = methyland R⁴ = hydrogen TBOC OH —S— X = Y = thiophen-3-yl Z = hydrogen 0 R³ =methyl and R⁴ = hydrogen TBOC OH —S(O)— X = Y = thiophen-3-yl Z =hydrogen 2 R³ = methyl and R⁴ = hydrogen TBOC OH —S(O)₂— X = Y =thiophen-3-yl Z = hydrogen 2 R³ = methyl and R⁴ = hydrogen TBOC OH—SCH₂CH₂— X = Y = thiophen-3-yl Z = hydrogen 0 R³ = R⁴ = CH₃; TBOC OH—CF₂CH₂— X = Y = thiophen-3-yl Z = hydrogen 1 R³ = R⁴ = hydrogen; TBOCOH —CFHCH₂— X = Y = thiophen-3-yl Z = hydrogen 1 R³ = R⁴ = hydrogen;—(C═O)—O—R¹ —O-phenethyl absent X = Y = thiophen-3-yl Z = hydrogen 3 R³= R⁴ = R¹ = cyclopentyl hydrogen; —(C═O)—O—R¹ —NH-phenethyl absent X = Y= thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = R¹ = cyclopentyl hydrogen;—(C═O)—O—R¹ —NHS(O)₂-phenethyl absent X = Y = thiophen-3-yl Z = hydrogen3 R³ = R⁴ = R¹ = cyclopentyl hydrogen; —(C═O)—O—R¹ —(C═O)—OH absent X =Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = R¹ = cyclopentyl hydrogen;—(C═O)—O—R¹ —(C═O)—O—phenethyl absent X = Y = thiophen-3-yl Z = hydrogen3 R³ = R⁴ = R¹ = cyclopentyl hydrogen; —(C═O)—O—R¹ —(C═O)—NH-phenethylabsent X = Y = thiophen-3-yl Z = hydrogen 3 R³ = R⁴ = R¹ = cyclopentylhydrogen; —(C═O)—O—R¹ —(C═O)—NH—S(O)₂-ben- absent X = Y = thiophen-3-ylZ = hydrogen 3 R³ = R⁴ = R¹ = cyclopentyl zyl hydrogen.

The following additional pyridazinone macrocyclic molecules of theinvention were made by the methods and procedures described herein.While stereochemistry is shown, the invention is not limited to thestereochemistry depicted. Those of ordinary skill in the art willreadily appreciate that other isomers of these compounds are also withinthe scope of the invention.

Additional compounds of the invention are those of formula I, II or II,wherein W is a substituted benzimidazolyl, including those wherein thebenzimidazolyl is substituted with 1 or 2 heteroaryl groups, each ofwhich may be independently substituted. Examples of such compoundsinclude:

According to an alternate embodiment, the pharmaceutical compositions ofthe present invention may further contain other anti-HCV agents.Examples of anti-HCV agents include, but are not limited to,α-interferon, β-interferon, ribavirin, and amantadine.

According to an additional alternate embodiment, the pharmaceuticalcompositions of the present invention may further contain other HCVprotease inhibitors.

According to yet another alternate embodiment, the pharmaceuticalcompositions of the present invention may further comprise inhibitor(s)of other targets in the HCV life cycle, including, but not limited to,helicase, polymerase, metalloprotease, and internal ribosome entry site(IRES).

According to a further embodiment, the present invention includesmethods of treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject an anti-HCV virally effectiveamount of the pharmaceutical compounds or compositions of the presentinvention. The methods can further include administration of anadditional therapeutic agent, including another antiviral agent or ananti-HCV agent. The additional agent can be co-administered,concurrently administered or sequentially administered with the compoundor composition delineated herein. The methods herein can further includethe step of identifying that the subject is in need of treatment forhepatitis C infection. The identification can be by subjective (e.g.,health care provider determination) or objective (e.g., diagnostic test)means.

All references, including patents, patent publications, articles, texts,etc. disclosed throughout this specification are hereby incorporated byreference in their entirety.

Definitions

The following definitions of various terms and phrases used to describethe invention are consistent with their normal use in the art and applyto the terms as they are used throughout this specification and claimsunless otherwise limited in specific instances, either individually oras part of a larger group.

The term “C_(x)-C_(y),” as used herein, is used in conjunction with thename of a carbon-containing group to indicate that the group containsfrom x to y carbon atoms where x and y are whole numbers.

The term “halo” and “halogen,” as used herein, refer to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The term “alkyl,” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. Examples include, but are notlimited to methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, octyl, decyl, dodecyl radicals.

The term “substituted alkyl,” as used herein, refers to an “alkyl” groupsubstituted by independent replacement of one or more (e.g., 1, 2, or 3)of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN,C_(I)-C₆-alkyl-OH, C(O)—C_(I)-C₆-alkyl, OCH₂—(C₃-C₁₂-cycloalkyl),C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—(C_(I)-C₆-alkyl), CONH-aryl, CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl),OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCON—(C_(I)-C₆-alkyl), OCONH-aryl, OCONH-heteroaryl,NHC(O)—(C₁-C₆-alkyl), NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—(C_(I)-C₆-alkyl),NHCONH-aryl, NHCONH-heteroaryl, SO₂—C₁-C₆ alkyl, SO₂-aryl,SO₂-heteroaryl, SO₂NH₂, SO₂NH—C_(I)-C₆-alkyl, SO₂NH-aryl,SO₂NH-heteroaryl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂,CH₂NH₂,CH₂SO₂CH₃H, C_(I)-C₆ alkyl, halo alkyl, C₃-C₁₂ cycloalkyl,substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C_(I)-C₃-alkylamino,thio, aryl-thio, heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, ormethylthiomethyl.

The term “haloalkyl,” as used herein, refers to an acyclic, straight orbranched chain alkyl substituent having one or more hydrogen substitutedfor a halogen selected from bromo, chloro, fluoro, or iodo.

The term “thioalkyl,” as used herein, refers to an acyclic, stright orbranched chain alkyl substituent containing a thiol group, such as, forexample and not limitation, thiopropyl.

The term “alkoxy,” as used herein, refers to an alkyl group, aspreviously defined, attached to the parent molecular moiety through anoxygen atom. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxyand n-hexoxy.

The term “alkenyl,” as used herein, denotes a monovalent group derivedby the removal of a single hydrogen atom from a hydrocarbon moietyhaving at least one carbon-carbon double bond. Alkenyl groups include,but are not limited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, and the like.

The term “substituted alkenyl,” as used herein, refers to an “alkenyl”group substituted by independent replacement of one or more of thehydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN,C_(I)-C₆-alkyl-OH, C(O)—(C_(I)-C₆-alkyl), OCH₂—(C₃-C₁₂-cycloalkyl),C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C_(I)-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl),OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl,OCO₂-heteroaryl,OCONH₂, OCONH—C_(I)-C₆-alkyl, OCONH-aryl,OCONH-heteroaryl, NHC(O)—C₁-C₆-alkyl,NHC(O)-aryl, NHC(O)-heteroaryl,NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—(C_(I)-C₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl,SO₂—(C_(I)-C₆-alkyl), SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl, SO₂NH-heteroaryl, C_(I)-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂, CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆alkyl, halo alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy,C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino,arylamino, heteroarylamino, C_(I)-C₃-alkylamino, thio, aryl-thio,heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, or methylthiomethyl.

The term “alkynyl,” as used herein, denotes a monovalent group derivedby the removal of a single hydrogen atom from a hydrocarbon moietyhaving at least one carbon-carbon triple bond. Representative alkynylgroups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, and the like.

The term “substituted alkynyl,” as used herein, refers to an “alkynyl”group substituted by independent replacement of one or more of thehydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN,C_(I)-C₆-alkyl-OH, C(O)—(C_(I)-C₆-alkyl), OCH₂—(C₃-C₁₂-cycloalkyl),C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—(C_(I)-C₆-alkyl), CONH-aryl, CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl),OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—(C_(I)-C₆-alkyl), OCONH-aryl, OCONH-heteroaryl,NHC(O)—(C_(I)-C₆-alkyl), NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—(C_(I)-C₆-alkyl),NHCONH-aryl, NHCONH-heteroaryl, SO₂—(C_(I)-C₆-alkyl), SO₂-aryl,SO₂-heteroaryl, SO₂NH₂, SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl,SO₂NH-heteroaryl, C_(I)-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂,CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆ alkyl, halo alkyl, C₃-C₁₂ cycloalkyl,substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C_(I)-C₃-alkylamino,thio, aryl-thio, heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, ormethylthiomethyl.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetra hyd rona phthyl, indanyl, idenyland the like.

The term “substituted aryl,” as used herein, refers to an aryl group, asdefined herein, substituted by independent replacement of one or more ofthe hydrogen atoms thereon with F, Cl, Br, I, OH, NO₂, CN,C₁-C₆-alkyl-OH, C(O)—(C_(I)-C₆-alkyl), OCH₂—(C₃-C₁₂-cycloalkyl),C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—(C_(I)-C₆-alkyl), CONH-aryl, CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl),OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—(C_(I)-C₆-alkyl), OCONH-aryl, OCONH-heteroaryl,NHC(O)—(C_(I)-C₆-alkyl), NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—(C_(I)-C₆-alkyl),NHCONH-aryl, NHCONH-heteroaryl, SO₂—(C_(I)-C₆-alkyl), SO₂-aryl,SO₂-heteroaryl, SO₂NH₂, SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl,SO₂NH-heteroaryl, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂,CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆ alkyl, halo alkyl, C₃-C₁₂ cycloalkyl,substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C₁-C₆-alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C_(I)-C₃-alkylamino,thio, aryl-thio, heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, ormethylthiomethyl.

The term “arylalkyl,” as used herein, refers to a CI-C3 alkyl or CI-C6alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “substituted arylalkyl,” as used herein, refers to an arylalkylgroup, as previously defined, substituted by independent replacement ofone or more of the hydrogen atoms thereon with F, Cl, Br, I, OH, NO₂,CN, C_(I)-C₆-alkyl-OH, C(O)—C_(I)-C₆-alkyl, OCH₂—(C₃-C₁₂-cycloalkyl),C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl, CO₂-aryl, CO₂-heteroaryl, CONH₂,CONH—C_(I)-C₆-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl),OC(O)-aryl, OC(O)-heteroaryl, OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl,OCONH₂, OCONH—(C_(I)-C₆-alkyl), OCONH-aryl, OCONH-heteroaryl,NHC(O)—(C_(I)-C₆-alkyl), NHC(O)-aryl, NHC(O)-heteroaryl, NHCO₂-alkyl,NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂, NHCONH—(C_(I)-C₆-alkyl),NHCONH-aryl, NHCONH-heteroaryl, SO₂—(C_(I)-C₆-alkyl), SO₂-aryl,SO₂-heteroaryl, SO₂NH₂, SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl,SO₂NH-heteroaryl, C_(I)l-C₆-alkyl, C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂,CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆ alkyl, halo alkyl, C₃-C₁₂ cycloalkyl,substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocycloalkyl, benzyl, benzyloxy,aryloxy, heteroaryloxy, C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy,amino, benzylamino, arylamino, heteroarylamino, C_(I)-C₃-alkylamino,thio, aryl-thio, heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, ormethylthiomethyl.

The term “cycloalkyl” denotes a monovalent group derived by the removalof a single hydrogen atom from a monocyclic or bicyclic saturatedcarbocyclic ring compound. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl.

The term “substituted cycloalkyl,” as used herein, refers to acycloalkyl group as defined herein, substituted by independentreplacement of one, two or three of the hydrogen atoms thereon with F,Cl, Br, I, OH, NO₂, CN, C_(I)-C₆-alkyl-OH, C(O)—(C_(I)-C₆-alkyl),OCH₂—(C₃-C₁₂-cycloalkyl), C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl,CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—(C_(I)-C₆-alkyl), CONH-aryl,CONH-heteroaryl, OC(O)—(C₁-C₆-alkyl), OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO2-heteroaryl, OCONH2, OCONH—CI—C6-alkyl,OCONH-aryl, OCONH-heteroaryl, NHC(O)—(C_(I)-C₆-alkyl, NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—(C_(I)-C₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl,SO₂—(C_(I)-C₆-alkyl), SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl, SO₂NH-heteroaryl, C_(I)-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂, CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆alkyl, halo alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy,C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino,arylamino, heteroarylamino, C_(I)-C₃-alkylamino, thio, aryl-thio,heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, or methylthiomethyl.

The terms “heterocyclo” and “heterocyclic” as used herein, refer to amonovalent substituent derived by removal of a hydrogen from a three toseven-membered saturated or unsaturated (including aromatic) cyclehaving 1 to 4 non-carbon ring atoms selected from the heteroatomsconsisting of N, O, and S. Examples of suitable heterocycles include butare not limited to tetrahydrofuran, thiophene, diazepine, isoxazole,piperidine, dioxane, morpholine, and pyrimidine. The term also includesa heterocycle as defined herein fused to one or more other cycleswhether hetero or carbocyclic. One example is thiazolo[4,5-b]-pyridine.Although the terms “heterocycloalkyl,” “aliphatic heteromonocyclic ringsystem,” “aliphatic heterobicyclic ring system,” “aliphaticheterotricyclic ring system,” “heteroaryl,” “aromatic heteromonocyclicring system,” “aromatic heterobicyclic ring system,” “aromaticheterotricyclic ring system,” “heteroarylalkyl,” are covered generallyby the term “heterocycle,” their specific meanings are set forth infurther detail below.

The term “heterocycloalkyl,” as used herein, refers to a non-aromatic5-, 6- or 7-membered ring or a bi- or tri-cyclic group comprising fusedsix-membered rings having between one and three heteroatomsindependently selected from oxygen, sulfur and nitrogen, wherein (i)each 5-membered ring has 0 to 1 double bonds and each 6-membered ringhas 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms mayoptionally be oxidized, (iii) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above heterocyclic rings may be fusedto a benzene ring. Representative heterocycles include, but are notlimited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, and tetra hydrofuryl.

The term “substituted heterocycloalkyl,” as used herein, refers to aheterocycloalkyl group, as previously defined, substituted byindependent replacement of one or more of the hydrogen atoms thereonwith F, Cl, Br, I, OH, NO₂, CN, C₁-C₆-alkyl-OH, C(O)—C_(I)-C₆-alkyl,OCH₂—(C₃-C₁₂-cycloalkyl), C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl,CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C_(I)-C₆-alkyl, CONH-aryl,CONH-heteroaryl, OC(O)—C₁-C₆-alkyl, OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—(C_(I)-C₆-alkyl),OCONH-aryl, OCONH-heteroaryl, NHC(O)—(C₁-C₆-alkyl), NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—(C_(I)-C₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl,SO₂—(C_(I)-C₆-alkyl), SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl, SO₂NH-heteroaryl, C—C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂, CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆alkyl, halo alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy,C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino,arylamino, heteroarylamino, C_(I)-C₃-alkylamino, thio, aryl-thio,heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, or methylthiomethyl.

As used herein, the term “aliphatic heteromonocyclic ring system” isintended to mean a ring system containing a non-aromatic ring thatincludes at least one ring hetero (i.e., non-carbon) atom selected fromO, N and S. The term “aliphatic heterobicyclic ring system” is intendedto mean a ring system containing a two fused rings, at least one ofwhich is a non-aromatic ring that includes at least one ring hetero(i.e., non-carbon) atom selected from O, N and S. The term “aliphaticheterotricyclic ring system” is intended to mean a ring systemcontaining three fused rings, at least one of which is a non-aromaticring that includes at least one ring hetero (i.e., non-carbon) atomselected from O, N and S. As will be appreciated, the aliphaticheterocyclic ring systems can possess any degree of saturation (i.e.,double or triple bonds) provided that none of the heteroatom-containingconstituent rings are aromatic. Thus, structures such as indoline, whichcontains a non-aromatic heterocyclic ring (i.e., a pyrroline ring) fusedto an aromatic carbocyclic ring (specifically, a phenyl ring), andphthalimide, are examples of an “aliphatic heterobicyclic ring systems.”

As used herein, the term “aromatic heteromonocyclic ring system” isintended to mean an aromatic ring that includes at least one ring hetero(i.e., non-carbon) atom selected from O, N and S. The term “aromaticheterobicyclic ring system” is intended to mean an aromatic ring systemcontaining two fused rings that includes at least one ring hetero (i.e.,non-carbon) atom selected from O, N and S. The term “aromaticheterotricyclic ring system” is intended to mean an aromatic ring systemcontaining three fused rings that includes at least one ring hetero(i.e., non-carbon) atom selected from O, N and S. Substituent atoms ofthe aromatic heterocyclic ring systems can, together with additionalatoms, form further fused ring structures that are not aromatic. Thus,5,6, 7,8 tetrahydroisoquinoline is an example of an aromaticheterobicyclic ring system, whereas 1,2,3,4 tetrahydroisoquinoline is anexample of an aliphatic heterobicyclic ring system.

The term “heteroaryl,” as used herein, refers to a cyclic aromaticradical having from five to ten ring atoms of which at least one ringatom is selected from S, O and Nand the remaining ring atoms are carbon,the radical being joined to the rest of the molecule via any of the ringatoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, and the like.

The term “substituted heteroaryl,” as used herein, refers to aheteroaryl group as defined herein, substituted by independentreplacement of one, two or three of the hydrogen atoms thereon with F,Cl, Br, I, OH, NO₂, CN, C_(I)-C₆-alkyl-OH, C(O)—C_(I)-C₆-alkyl,OCH₂—(C₃-C₁₂-cycloalkyl), C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl,CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—(C_(I)-C₆-alkyl), CONH-aryl,CONH-heteroaryl, OC(O)—(C₁-C₆)-alkyl, OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—(C_(I)-C₆-alkyl),OCONH-aryl, OCONH-heteroaryl, NHC(O)—(C_(I)-C₆-alkyl), NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—(C_(I)-C₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl,SO₂—(C_(I)-C₆-alkyl), SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl, SO₂NH-heteroaryl, C_(I)-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂, CH₂NH₂, CH_(SO) ₂CH₃H, C1-C6alkyl, halo alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy,C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino,arylamino, heteroarylamino, C_(I)-C₃-alkylamino, thio, aryl-thio,heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, or methylthiomethyl.

The term “heteroarylalkyl,” as used herein, refers to a C_(I)-C₃ alkylor C₁-C₆ alkyl residue attached to a heteroaryl ring. Examples include,but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.

The term “substituted heteroarylalkyl,” as used herein, refers to aheteroarylalkyl group, as previously defined, substituted by independentreplacement of one or more of the hydrogen atoms thereon with F, Cl, Br,I, OH, NO₂, CN, C₁-C₆-alkyl-OH, C(O)—C_(I)-C₆-alkyl,OCH₂—(C₃-C₁₂-cycloalkyl), C(O)-aryl, C(O)-heteroaryl, CO₂-alkyl,CO₂-aryl, CO₂-heteroaryl, CONH₂, CONH—C_(I)-C₆-alkyl, CONH-aryl,CONH-heteroaryl, OC(O)—C₁-C₆-alkyl, OC(O)-aryl, OC(O)-heteroaryl,OCO₂-alkyl, OCO₂-aryl, OCO₂-heteroaryl, OCONH₂, OCONH—(C_(I)-C₆-alkyl),OCONH-aryl, OCONH-heteroaryl, NHC(O)—(C₁-C₆-alkyl), NHC(O)-aryl,NHC(O)-heteroaryl, NHCO₂-alkyl, NHCO₂-aryl, NHCO₂-heteroaryl, NHCONH₂,NHCONH—(C_(I)-C₆-alkyl), NHCONH-aryl, NHCONH-heteroaryl,SO₂—(C_(I)-C₆-alkyl), SO₂-aryl, SO₂-heteroaryl, SO₂NH₂,SO₂NH—(C_(I)-C₆-alkyl), SO₂NH-aryl, SO₂NH-heteroaryl, C_(I)-C₆-alkyl,C₃-C₆-cycloalkyl, CF₃, CH₂CF₃, CHC1₂, CH₂NH₂, CH₂SO₂CH₃H, C_(I)-C₆alkyl, halo alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,aryl, substituted aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, benzyl, benzyloxy, aryloxy, heteroaryloxy,C_(I)-C₆-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino,arylamino, heteroarylamino, C_(I)-C₃-alkylamino, thio, aryl-thio,heteroarylthio, benzyl-thio, C_(I)-C₆-alkyl-thio, or methylthiomethyl.

Substituent groups substituted on any group (e.g., alkyl, alkenyl,alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heterocyclic)delineated herein also include any of —F, —Cl, —Br, —I, —OH, protectedhydroxy, aliphatic ethers, aromatic ethers, oxo, —NO₂, —CN,—C₁-C₁₂-alkyl optionally substituted with halogen (such asperhaloalkyls), C₂-C₁₂-alkenyl optionally substituted with halogen,—C₂-C₁₂-alkynyl optionally substituted with halogen, —NH₂, protectedamino, —NH—C₁-C₁₂-alkyl, —NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₁₂-alkenyl, —O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH—C₂-C₁₂-alkynyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —CO₂—C₁-C₁₂-alkyl, —CO₂-C₂-C₁₂-alkenyl,—CO₂—C₂-C₁₂-alkynyl, —CO₂—C₃-C₁₂-cycloalkyl, —CO₂-aryl, —CO₂-heteroaryl,—CO₂-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₁₂-alkenyl,—OCO₂—C₂-C₁₂-alkynyl, −OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₁₂-alkenyl, —OCONH—C₂-C₁₂-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₁₂-alkenyl,—NHCO₂—C₂-C₁₂-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl,—NHC(O)NH—C₂-C₁₂-alkynyl, —NHC(O)N—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₁₂-alkenyl,—NHC(S)NH—C₂-C₁₂-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₁₂-alkenyl,—NHC(NH)NH—C₂-C₁₂-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl,—NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)-C₁₂-C₁₂-alkenyl,—S(O)-C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂-C₂-C₁₂-alkynyl,—NHSO₂-C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkylsand the like can be further substituted.

The term “alkylamino,” as used herein, refers to a group having thestructure —NH(C₁-C₁₂ alkyl) where C_(I)-C₁₂ alkyl is as previouslydefined. The term “dialkylamino” refers to a group having the structure—N(C₁-C₁₂ alkyl)₂ where C_(I)-C₁₂ alkyl is as previously defined.Examples of dialkylamino are, but not limited to, N,N-dimethylamino,N,N-diethylamino, N,N-methylethylamino, piperidino, and the like.

The term “diarylamino” refers to a group having the structure —N(aryl)₂or —N(substituted aryl)₂ where substituted aryl is as previouslydefined. Examples of diarylamino are, but not limited to,N,N-diphenylamino, N,N-dinapthylamino, N,N-di(toluenyl)amino, and thelike.

The term “diheteroarylamino” refers to a group having the structure—N(heteroaryl)₂ or —N(substituted heteroaryl)₂, where heteroaryl andsubstituted heteroaryl is as previously defined. Examples ofdiheteroarylamino are, but not limited to, N,N-difuranylamino,N,N-dithiazolidinylamino, N,N-di(imidazole)amino, and the like.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3 -butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bn or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethyisilyl, triethylsilyl, methoxymethyl groups,for example.

The term “nitrogen (or amino) protecting group,” as used herein, refersto a labile chemical moiety which is known in the art to protect anitrogen group against undesired reactions during synthetic procedures.After said synthetic procedure(s) the nitrogen protecting group asdescribed herein may be selectively removed. Nitrogen protecting groupsas known in the are described generally in T. H. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley &Sons, New York (1999). Examples of nitrogen protecting groups include,but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “nucleophilic heterocyclic compound” refers to a heterocyclicgroup in a nucleophilic form (e.g., metal salt form, protonated form)such that it is capable of reacting with another molecule resulting in acovalent bond between the two molecules (e.g., a nucleophile in anucleophilic displacement reaction). Examples of such nucleophilicheterocyclic compounds are known in the art and delineated herein.

The term “leaving group: refers to a moiety that can be detached from amolecule during a reaction, especially nucleophilic displacementreactions. Examples of leaving groups include, for example, halides,mesyl groups, tosyl groups, alkoxides, hydroxides, and protonated formsthereof. Examples of such leaving groups are known in the art anddelineated herein.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protogenic organic solvent,” as used herein, refers to asolvent that tends to provide protons, such as an alcohol, for example,methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and thelike. Such solvents are well known to those skilled in the art, and itwill be obvious to those skilled in the art that individual solvents ormixtures thereof may be preferred for specific compounds and reactionconditions, depending upon such factors as the solubility of reagents,reactivity of reagents and preferred temperature ranges, for example.Further discussions of protogenic solvents may be found in organicchemistry textbooks or in specialized monographs, for example: OrganicSolvents Physical Properties and Methods of Purification, 4th ed.,edited by John A. Riddick et al., Vol. II, in the Techniques ofChemistry Series, John Wiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The term “subject” as used herein refers to a mammal. Preferably themammal is a human. A subject also refers to, for example, dogs, cats,horses, cows, pigs, guinea pigs and the like.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting the free base function with a suitable organic acid. Examplesof pharmaceutically acceptable, nontoxic acid addition salts include,but are not limited to, salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include, but arenot limited to, adipate, alginate, ascorbate, aspartate,benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,camphorsulfonate, citrate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C_(I)-C₆ sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, but are not limited to, those derivedfrom pharmaceutically acceptable aliphatic carboxylic acids,particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, inwhich each alkyl or alkenyl moiety advantageously has not more than 6carbon atoms. Examples of particular esters include, but are not limitedto, formates, acetates, propionates, butyates, acrylates andethylsuccinates.

The term “pharmaceutically acceptable prodrugs,” as used herein, refersto those prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, commensurate with areasonable risk/reward ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formulae,for example, by hydrolysis in blood. A thorough discussion is providedin T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14of the A.C.S. Symposium Series and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design (American PharmaceuticalAssociation and Pergamon Press, 1987), both of which are incorporated byreference herein.

The term “effective amount” or “therapeutically effective amount,” asused herein, means an amount which is capable of inhibiting the HCV NS3serine protease, therefore interfering with the production of the viralpolyprotein essential for viral replication. The HCV serine proteaseinhibition contemplated by the present method includes both therapeuticand prophylactic treatment, as appropriate for the subject in need ofsuch treatment. Methods of treatment, dosage levels and requirements maybe selected by those of ordinary skill in the art from available methodsand techniques. For example, a compound of the present invention may becombined with a pharmaceutically acceptable excipient for administrationto a virally-infected patient in a pharmaceutically acceptable mannerand in an amount effective to lessen the severity of the viralinfection. Alternatively, the compounds of the present invention may beused in vaccines and methods for protecting individuals against HCVviral infection over an extended period of time. The compounds may beemployed in a manner consistent with the conventional utilization ofprotease inhibitors in vaccines. For example, a compound of the presentinvention may be combined with pharmaceutically acceptable excipientsconventionally employed in vaccines and administered in prophylacticallyeffective amounts to protect individuals over an extended period of timeagainst HCV viral infection. As such, the protease inhibitors of thepresent invention can be administered as agents for treating orpreventing HCV viral infection in a subject.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain two or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers Racernates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. SomeExamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil ; corn oil and soybean oil;glycols; such a propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents, commonly used in the art such as, forexample, water or other solvents, solubilizing agents and 30 emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention. Theointments, pastes, creams and gels may contain, in addition to an activecompound of this invention, excipients such as animal and vegetablefats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Antiviral Activity

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject, such as a human orlower mammal, by administering to the subject an effective amount of acompound of the invention, in such amounts and for such time as isnecessary to achieve the desired result. The term “anti-hepatitis Cvirally effective amount” of a compound of the invention, as usedherein, means a sufficient amount of the compound so as to decrease theviral load in a subject, thus decreasing said subject's chronic HCVsymptoms. As well understood in the medical arts an anti-hepatitis Cvirally effective amount of a compound of this invention will be at areasonable benefit/risk ratio applicable to any medical treatment.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific anti-HCV virally effective dose level for any particularpatient will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; the activity of thespecific compound employed; the specific composition employed; the age,body weight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts.

The total daily dose of the compounds of this invention administered toa subject in single or in divided doses can be in amounts, for example,from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kgbody weight. Single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in single or multiple doses.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

-   -   ACN for acetonitrile;    -   BME for 2-mercaptoethanol;    -   BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium        hexafluorophosphate;    -   COD for cyclooctadiene;    -   DABCYL for        6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;    -   DAST for diethylaminosulfur trifluoride;    -   DCM for dichloromethane;    -   DIAD for diisopropyl azodicarboxylate;    -   DIBAL-H for diisobutylaluminum hydride;    -   DIEA for diisopropyl ethylamine;    -   DMAP for N,N-dimethylaminopyridine;    -   DME for ethylene glycol dimethyl ether;    -   DMEM for Dulbecco's Modified Eagles Media;    -   DMF for N,N-dimethyl formamide;    -   DMSO for dimethylsulfoxide;    -   DUPHOS for    -   EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;    -   EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide        hydrochloride;    -   EtOAc for ethyl acetate;    -   HATU for O        (7-Azabenzotriazole-1-yl)-N,N,N′,N+-tetramethyluronium        hexafluorophosphate;    -   HMBA is 4-Hydroxymethylbenzoic acid AM resin;    -   Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)        (tricyclohexylphosphine)ruthenium(II);    -   KHMDS is potassium bis(trimethylsilyl) amide;    -   Ms for mesyl;    -   NMM for N-4-methylmorpholine    -   Ph for phenyl;    -   PuPHOS    -   PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;    -   RCM for ring-closing metathesis;    -   RT for room temperature;    -   RT-PCR for reverse transcription-polymerase chain reaction;    -   tBOC or Boc for tert-butyloxy carbonyl;    -   TEA for triethyl amine;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TLC for thin layer chromatography;    -   TPP or PPh3 for triphenylphosphine; and    -   Xantphos for        4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene.

Certain chemical structures herein having —NH or —OH groups appearwithout those hydrogen atoms attached to oxygen or nitrogen atomsdepicted. Thus, where a nitrogen or oxygen atom in such structureappears to lack proper valency, the presence of those hydrogen atoms areimplied.

SYNTHETIC METHODS

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the invention may beprepared.

I. Replacement Method

Compounds of the present invention can be made via a replacementprocedure described generally in the following scheme:

The hydroxyl proline or mesylated proline precursor may be used. Thisreplacement method protocol is suitable for converting any hydroxy (orcorresponding mesylate) proline compound or derivative starting compoundto a heterocyclic substituted proline derivative. The subsequentsynthetic methods set forth the various procedures and intermediatesteps that may be used to prepare the compounds disclosed herein.

A. Synthesis Of Hydroxyl Proline Cyclic Peptide Precursors

A cyclic peptide precursor may be used to synthesize the compounds ofthe invention. In some embodiments, a mesylated version of the cyclicprecursor may be used.

In some embodiments, commercially available Boc-hydroxyproline A

s treated with HCl in dioxane to yield starting material Ib.Synthesis of Cyclic Peptide Precursor

The cyclic peptide precursor Ig was synthesized fromBoc-L-2-amino-8-nonenoic acid Ia and cis-L-hydroxyproline methyl esterIb via steps A-D set forth generally in Scheme 1. For further details ofthe synthetic methods employed to produce the cyclic peptide precursorIg, see U.S. Pat. No. 6,608,027, which is herein incorporated byreference in its entirety.Synthesis of Mesylate of Macrocyclic Peptide Precursor

The cyclic precursor mesylate was synthesized by forming the mesylateupon the hydroxyl of the hydroxyl proline residue of the cyclic peptideprecursor via the synthetic route generally described above in Scheme 2.

The compounds of the present invention are made via the replacement ofthe mesylate of the macrocyclic peptide mesylate IIa with a5-substituted-2H-tetrazole, Exemplary syntheses of such tetrazoloes asdescribed in Scheme 5, below, via the synthetic route describedgenerally in Scheme 3.

The compounds of the present invention are made via the replacement ofthe mesylate of the macrocyclic peptide mesylate IIa with a4,5-substituted-1 H-triazole via the synthetic route described generallyin Scheme 4. Exemplary syntheses of such triazoles are described inscheme 6, below.

B. Synthesis of Substitutes for W

W may be any of the substitutents described previously herein. Synthesisof these various substituents is within the skill of those of ordinaryskill in the art. Some exemplary syntheses are presented herein by wayof example and not of limitation. Other substituents are eithercommercially available or readily synthesized by those of ordinary skillin the art.

Synthesis of Tetrazoles

Structurally diverse tetrazoles Va-Vq were synthesized from commerciallyavailable nitrile compounds as described in Scheme 5 below:

One skilled in the art will recognize that several 5-substitutedtetrazole compounds may be produced in this manner with anynitrile-containing compound suitable for the reaction conditions setforth above.Synthesis of triazoles

Triazoles of the present invention are prepared by reacting alkynecompound VIa, which is commercially available or made from procedureselucidated infra, and trimethylsilyl azide via the synthetic routedescribed generally in Scheme 6. Commercially available alkynes suitablefor triazole formation include, but are not limited to:

Synthesis of Alkynes

Alkynes useful in the synthesis of triazoles may be made by anyappropriate method. Below are some exemplary syntheses.

Sonogashira Reaction

Alkynes used in the present invention can be made by the Sonogashirareaction with primary alkyne compound VIIa, an aryl halide (Y-halide),and triethylamine in acetonitrile with PdCl₂(PPh₃)₂ and Cul via thesynthetic route described generally in Scheme 7.

Commercially-available aryl halides suitable for the Sonogashirareaction include, but are not limited to:

Commercially-available primary alkynes suitable for the Sonogashirareaction include, but are not limited to:

Synthesis of Alkynyl Amides

Additional alkynes used in the present invention can be made by reactingalkynyl acid Va, BOP, and DIEA in DMF with amine VIIIb via the syntheticroute described generally in Scheme 8.

Post-Replacement Modification

The resultant macrocyclcic compound may be modified after W is attached.Some exemplary modifications follow.

1. Synthesis of Phenolic Esters

The post-replacement modification of macrocyclic compound IIIa to obtainvarious phenolic esters was performed by the synthetic route describedgenerally in Scheme 9.

2. Hydrolysis of Macrocyclic Peptide Ethyl Ester

The hydrolysis of macrocyclic peptide ethyl esters of the presentinvention is performed by dissolving macrocyclic peptide ethyl ester IVin dioxane and adding 1M LiOH via the synthetic route describedgenerally in Scheme 10.

3. Using Suzuki Coupling to Generate More Bi-Aryl Compounds

Compounds of the present invention may be further diversified byperforming a Suzuki coupling adding to bromo-substituted triazolemacrocyclic ethyl ester (see infra Example 26 for preparation) DME anaromatic boric acid, cesium carbonate and KF via the synthetic routedescribed generally in Scheme 11.

II. Stepwise Synthesis

Compounds of the invention may also be prepared though a stepwisesynthesis rather than a replacement mechanism. Below is an exemplarysynthesis where W is a tetrazole.

A. Synthesis of Proline Derivatives.

B. Synthesis of Linear Tripeptides.

The linear tri-peptide containing tetrazole-substituted prolinederivatives XIIc were prepared via the synthetic route describedgenerally in Scheme 12.

C. Synthesis of Cyclic Peptide Via Ring-Closing-Metathesis (RCM).

Formation of macrocyclic compound Xb was performed using lineartripeptide XIIId via the Ring-Closing Metathesis reaction describedgenerally in Scheme 14.

D. Other Derivatives

1. Tetrazole-substituted proline derivatives of the present inventionwere synthesized by the synthetic route described generally in Scheme12.

Additional tetrazole-substituted proline derivatives of the presentinvention were synthesized by the synthetic route described generally inScheme 15.

2. Suzuki Coupling

Further derivatives were prepared using the Suzuki Coupling reactiondescribed generally in Scheme 16.

III. Solid Phase Synthesis

Some compounds of the invention are amenable to synthesis by solid phasesynthesis. For example, the triazole-substituted proline derivatives(P2) can be synthesized and used in an on-resin assembly of a lineartripeptide chain. The resin-bound tripeptides, containing thetriazole-substituted proline derivatives, undergoRing-Closing-Metathesis (RCM) to furnish a cyclic tripeptide that iscleaved from the resin by hydrolysis affording the final product.

The following synthetic schemes set forth manners in which thetriazole-substituted proline derivatives are made and the solid-phasesynthesis of the compounds of the present invention.

A. Synthesis of Proline Derivatives

Two methods were employed to synthesize the triazole-substituted prolinederivatives which are described generally by the following schemes:

1. Cyclo-Addition Method

The cyclo-addition method to create triazolyl proline derivativesinvolves the 3+2 cyclo-addition of azide proline derivative XVIIb andalkyne VIIb via the synthetic route described generally in Scheme 17.Exemplary syntheses of alkynes are described in Scheme 7 above.

2. Mesylate Method

Additional proline derivatives were synthesized via the replacement ofmesylate XVIIIa with a 4,5-substituted-1H-triazole via the syntheticroute described generally in Scheme 18.

B. On-Resin Assembly and On-Resin RCM

On Resin Assembly

The on-resin assembly of linear peptide XIXd followed by the on-resinRCM to obtain resin-bound cyclic peptide precursor XIXe was performedvia steps A-D described generally in Scheme 19.

IV. Other Reactions

In some embodiments, the substituent W is well-suited to other types ofreactions. For example, and not by limitation, when W is a pyridazinone,the following reaction schemes are used. These methods may be used forother substituents, but are discussed here in the context ofpyridazinones.

A. Condensation Reactions

The simplest method, shown in Scheme 20, is to condense commerciallyavailable pyridazinones (XXa-1-XXa-4) with key intermediate If by usingMitsunobu conditions followed by hydrolysis with LiOH. For furtherdetails on the Mitsunobu reaction see O. Mitsunobu, Synthesis 1981,1-28; D. L. Hughes, Org. React. 29, 1-162 (1983); D. L. Hughes, OrganicPreparations and Procedures Int. 28, 127-164 (1996); and J. A. Dodge, S.A. Jones, Recent Res. Dev. Org. Chem. 1, 273-283 (1997).

The second method of preparing pyridazinone analogs of the presentinvention is to further chemically manipulate di-bromo intermediate XXIa(Scheme 21). The standard Mitsunobu coupling of the commerciallyavailable 4,5-dibromopyridazinone with hydroxyl If afforded the desiredmacrocycle XXIa. Coupling of XXIa with excess 3-thiophene boronic acid,cesium carbonate and potassium fluoride furnished di-thiophene XXIb.Hydrolysis of compound compounds XXIa and XXIb with LiOH gave thedesired analogs XXId and XXIc respectively. Many different boronic acidsmay be used in a similar manner to yield a plethora of di-substitutedpyridazinonyl macrocycles.

B. Bromide Differentiation Reaction

Differentiation between the bromides on macrocyclic XXIa is achieved viaMichael addition. As shown in Scheme 22, commercially availablepyrrolidine is coupled with di-bromide to give compound XXIIa in 87%yield. The bromide moiety □ to the carbonyl is then under goes a Suzukicoupling reaction with 3-thiophene boronic acid to produce intermediateXXIIb, which is further treated with LiOH to afford analog XXIIc. Forfurther details concerning the Suzuki coupling reaction see A. Suzuki,Pure Appl. Chem. 63, 419-422 (1991) and A. R. Martin, Y. Yang, ActaChem. Scand. 47, 221-230 (1993).

C. Sulfur Containing Nucleophiles

While the secondary amine nucleophile pyrrolidine gave exclusiveaddition to the 5-bromide position on macrocycle XXIa, sulfur-containingnucleophiles did not exhibit the same selectivity as shown in Scheme 23.With sulfur-containing nucleophiles, addition on both bromines of XXIais observed together with the mono-coupled product XXIIa with only oneequivalent of mercaptopyrimidine. The separability of compounds XXIIIa,XXIIIB and starting material XXIa by flash column chromatography allowedfor a further Suzuki coupling of the mono-alkylated XXIIIa with3-thiophene boronic acid followed by hydrolysis of XXIIId with LiOH tofurnish analog XXIIIe. The di-alkylated product XXIIIb is alsohydrolyzed with LiOH to produce analog XXIIIc.

D. Suzuki Coupling with Boronic Acid

With only a limited number of boronic acids available for Suzukicoupling, other coupling methods such as Stille coupling and N-arylationusing Buchwald's chemistry were also explored (Scheme 24). Coupling ofintermediate XXIa with 2-stannylthiazole with Stille standard conditionsfollowed by hydrolysis afforded analog XXIVa. As for N-arylation,coupling of imidazole to di-bromide 6 proceeded smoothly. Unfortunately,hydrolysis with LiOH resulted in replacement of the imidazole moiety onposition 5 with a methoxy (XXIVb. For further details concerning Stillecoupling reactions see J. K. Stille, Angew. Chem. Int. Ed. 25, 508-524(1986); M. Pereyre et al., Tin in Organic Synthesis (Butterworths,Boston, 1987) pp 185-207 passim., and T. N. Mitchell, Synthesis 1992,803-815. For further details of the Buchwald reaction see J. F. Hartwig,Angew. Chem. Int. Ed. 37, 2046-2067 (1998).

E. Other Diversified Pyridazinone Analogs

Another method for diversifying pyridazinone analogs is outlined inScheme 25. Michael addition with sodium azide as the nucleophile todi-bromo XXIa yielded, as in the secondary amine case, only themono-coupled compound XXVa. Further Suzuki coupling with 3-thiopheneboronic acid produced azide XXVb. Compound XXVb is hydrolyzed to giveanalog XXVc. In addition, the azide moiety of compound XXVb is furtherconverted to tetrazole under standard conditions with sodium cyanide,followed by hydrolysis to provide analog XXVd.

F. Synthesis of 5,6 Pyridazinoyl Macrocycle

The synthesis of 5,6 pyridazinonyl macrocycle XXVIb is outlined inScheme 26. Commercially available 5-bromo-6-phenyl-2H-pyridazin-3-one iscondensed with key intermediate If via Mitsunobu conditions to givecompound XXVIa. Product XXVIa is further subjected to Suzuki couplingconditions with 3-thiophene boronic acid, followed by hydrolysis to givethe desired analog XXVb.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art. Such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1 Synthesis of the Cyclic Peptide Precursor

1A. To a solution of Boc-L-2-amino-8-nonenoic acid 1a (1.36 g, 5 mol)and the commercially available cis-L-hydroxyproline methyl ester 1b(1.09 g, 6 mmol) in 15 ml DMF, was added DIEA (4 ml, 4 eq.) and HATU (4g, 2 eq). The coupling was carried out at 0° C. over a period of 1 hour.The reaction mixture was diluted with 100 mL EtOAc, and followed bywashing with 5% citric acid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 mland brine 2×10 ml, respectively. The organic phase was dried overanhydrous Na₂SO₄ and then was evaporated, affording the dipeptide 1c(1.91 g, 95.8%) that was identified by HPLC (Retention time=8.9 min,30-70%, 90% B), and MS (found 421.37, M+Na⁺).

1B. The dipeptide 1c (1.91 g) was dissolved in 15 mL of dioxane and 15mL of 1 N LiOH aqueous solution and the hydrolysis reaction was carriedout at RT for 4 hours. The reaction mixture was acidified by 5% citricacid and extracted with 100 mL EtOAc, and followed by washing with water2×20 ml, 1M NaHCO₃ 2×20 ml and brine 2×20 ml, respectively. The organicphase was dried over anhydrous Na₂SO₄ and then removed in vacuum,yielding the free carboxylic acid compound 1d (1.79 g, 97%), which wasused for next step synthesis without need for further purification.

1C. To a solution of the free acid obtained above (1.77, 4.64 mmol) in 5ml DMF, D-β-vinyl cyclopropane amino acid ethyl ester 1e (0.95 g, 5mmol), DIEA (4 ml, 4 eq.) and HATU (4 g, 2 eq) were added. The couplingwas carried out at 0° C. over a period of 5 hours. The reaction mixturewas diluted with 80 mL EtOAc, and followed by washing with 5% citricacid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ and thenevaporated. The residue was purified by silica gel flash chromatographyusing different ratios of hexanes:EtOAc as elution phase(5:1→3:1→1:1→1:2→1:5). The linear tripeptide 1f was isolated as an oilafter removal of the elution solvents (1.59 g, 65.4%), identified byHPLC (Retention time=11.43 min) and MS (found 544.84, M+Na⁺).

1D. Ring Closing Metathesis (RCM). A solution of the linear tripeptide1f (1.51 g, 2.89 mmol) in 200 ml dry DCM was deoxygenated by bubblingN₂. Hoveyda's 1^(st) generation catalyst (5 mol % eq.) was then added assolid. The reaction was refluxed under N₂ atmosphere 12 hours. Thesolvent was evaporated and the residue was purified by silica gel flashchromatography using different ratios of hexanes:EtOAc as elution phase(9:1→5:1→3:1→1:1→1:2→1:5). The cyclic peptide precursor 1 was isolatedas a white powder after removal of the elution solvents (1.24 g, 87%),identified by HPLC (Retention time=7.84 min, 30-70%, 90% B), and MS(found 516.28, M+Na⁺). For further details of the synthetic methodsemployed to produce the cyclic peptide precursor 1, see U.S. Pat. No.6,608,027, which is herein incorporated by reference in its entirety.

Example 2 Synthesis of the Cyclic Peptide Precursor Mesylate

2A. To a solution of the macrocyclic peptide precursor 1 (500 mg, 1.01mmol) and DIEA (0.4 ml, 2 mmol) in 2.0 ml DCM, mesylate chloride (0.1ml) was added slowly at 0° C. where the reaction was kept for 3 hours.30 mL EtOAc was then added and followed by washing with 5% citric acid2×10 ml, water 2×10 ml, 1M NaHCO₃ 2×10 ml and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ andevaporated, yielding the title compound mesylate that was used for nextstep synthesis without need for further purification.

Example 3 Tetrazole Synthesis

Structurally diverse tetrazoles IIIa-IIIq, for use in preparingtetrazolyl macrocycles of the invention were synthesized fromcommercially available nitrile compounds as described below:

To a sealed tube containing 5 ml xylene, was added3-Cl-4-hydroxy-benzoacetonitile (0.31 g, 5 mol), NaN₃ (0.65 g, 10 mmol)and the triethylamine hydrochloride (0.52 g, 3 mmol). The mixture wasstirred vigorously at 140° C. over a period of 20-30 hours. The reactionmixture was then cooled and poured to a mixture of EtOAc (30 ml) andaqueous citric acid solution (20 mL). After washing with water 2×10 mland brine 2×10 ml, the organic phase was dried over anhydrous Na₂SO₄ andwas evaporated to a yellowish solid. After re-crystallization withEtOAc-hexanes, the tetrazole compound 3a was obtained in good yield (0.4g, 86%%), high purity (>90%, by HPLC), and identified by NMR and MS(found 197.35 and 199.38, M+H⁺).

Example 4 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

Proline Derivative Synthesis

To a solution of N-Boc-cis-hydroxyproline methyl ester 4a (10 g, 40.8mmol) and N,N-Diisopropylethyl amine (DIEA, 12 mL, 60 mmol) in 110 mL ofDCM, was added 3.85 mL of mesylate chloride (50 mmol) in a dropwisemanner and the resulting reaction mixture was stirred at 0° C. for 3hours. TLC (hexanes:ethyl acetate=1:1, v/v) showed that Boc-cis-Hyp-OMe4a was totally converted to its mesylate 4b. After the reaction wasdeemed complete by TLC, the reaction mixture was diluted with 100 mlEtOAc, washed with 5% citric acid 2×50 ml and brine 2×30 ml, and driedover anhydrous Na₂SO₄. Removal of solvents gave 13 g (98% yield)N-Boc-cis-4-mesylate-proline methyl ester 4b, which was used in Step Bwithout need for further purification.

To a solution of the mesylate 4b (0.65 g, 2 mmol) in 5 mL DMF, was added4 mmol of 5-phenyl-1H-tetrazole and anhydrous sodium carbonate (0.53 g,5 mmol). The resulting reaction mixture was stirred vigorously at 60° C.for 6-12 hours. TLC (hexanes:ethyl acetate=1:1, v/v) showed the mesylate4b was completely converted to trans 4-tetrazole-substituted prolinederivative 4c. After the reaction was deemed complete by TLC, thereaction mixture was diluted with 30 ml EtOAc and washed with 1 M Na₂CO₃(3×10 ml), water (3×10 ml), 5% citric acid (3×10 ml) and brine (3×10ml), respectively. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated in vacuo, giving the 5-phenyl tetrazole substituted prolinederivative 4c in excellent yield (94%) and high purity (>90%). 4c: 94%yield, [M+Na]⁺=396.39.

Synthesis of Linear Tripeptides

A. (1) The dipeptide 4e was prepared by dissolving 0.22 g (0.6 mmol) ofN-Boc-trans-4-(3-phenyl tetrazolyl)-proline methyl ester 4c in 6 mL ofdioxane and 2 mL of 1 N LiOH aqueous solution. The resulting reactionmixture was stirred at RT for 3-8 hours to allow the for the hydrolysisof the methyl ester. The reaction mixture was acidified by 5% citricacid, extracted with 40 mL EtOAc, and washed with water 2×20 ml, 1MNaHCO₃ 2×20 ml and brine 2×10 ml, respectively. The organic phase wasdried over anhydrous Na₂SO₄ and concentrated in vacuo, yielding the freecarboxylic acid compound (0.20 g, 92%), which was used for next stepsynthesis without need for further purification. (2) To a cooled (0° C.)solution of the free acid obtained above (0.20 g, 0.55 mmol) in 2 mlDMF, was added D-β-vinyl cyclopropane amino acid ethyl ester 4d (0.1 g,0.52 mmol), DIEA (0.4 ml, 4 eq.) and HATU (0.4 g, 2 eq). The resultingreaction mixture was stirred at 0° C. for 0.5-3 hours. The reactionmixture was diluted with 40 mL EtOAc, and washed with 5% citric acid2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml, and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated in vacuo, affording the dipeptide 4e (0.24 g, 94%),identified by HPLC (Retention time=10.03 min) and MS (found 519.22,M+Na⁺).

B. (1) Tripeptide 4g was prepared by deprotecting the amine of dipeptide4e (0.24 g, 0.49 mmol) in 2 mL TFA at 0° C. for 10 min. After removal ofTFA in vacuo, the free amine product was subjected to next couplingreaction directly. (2) To a cooled (0° C.) solution of the free aminecompound obtained above in 2 ml DMF, was added Boc-2-amino-8-nonenoicacid 4f (0.136 g, 0.50 mmol), DIEA (0.4 ml, 4 eq.) and HATU (0.4 g, 2eq). The coupling was carried out at 0° C. over a period of 0.5-3 hours.The reaction mixture was diluted with 40 mL EtOAc and washed with 5%citric acid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated in vacuo, affording tripeptide 4g (0.28 g, 88% for twosteps) that was identified by HPLC (Retention time=14.03 min), and MS(found 672.30, M+Na⁺).

Synthesis of Cyclic Peptide Via Ring-Closing-Metathesis (RCM).

A. A solution of linear tripeptide 4g (71 mg, 0.109 mmol) in 50 ml dryDCM was deoxygenated by bubbling N₂. To the resulting degassed solutionwas added Hoveyda's Cat. (5-10 mol % eq.) was as solid and the resultingreaction mixture was refluxed under N₂ over for 5-20 hours. The reactionmixture was then concentrated in vacuo and the residue was purified bysilica gel flash chromatography using different ratios of hexanes:EtOAcas elution phase (9:1→5:1→3:1→1:1→1:2). The macrocyclic peptide 4i wasisolated as a white powder by evaporation of the elution solvents (58mg, 85.5%), identified by HPLC (Retention time=11.80 min, 30-80%, 90%B), and MS (found 644.66, M+Na⁺).

IV. Hydrolysis of the Ethyl Ester

The title compound was prepared by dissolving compound 4i (20 mg) in 2mL of dioxane and 1 mL of 1 N LiOH aqueous solution. The resultingreaction mixture was stirred at RT for 4-8 hours. The reaction mixturewas then acidified with 5% citric acid, extracted with 10 mL EtOAc, andwashed with water 2×20 ml. The solvent was evaporated and the residuewas purified by HPLC on a YMC AQ12S11-0520WT column with a 30-80% (100%acetonitrile) gradient over a 20 min period. After lyophilization, titlecompound was obtained as a white amorphous solid.

[M+Na]+=616.72.

Example 5 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-bromophenyl, j=3, m=s=1, and R³═R⁴═H

5A. Proline Derivative Synthesis

The proline derivative of the present example was prepared by theprocedure set forth in Example 4 (I) with 5-(2-bromophenyl)-1H-tetrazoleand N-Boc-cis-hydroxyproline methyl ester 4a.

[M+Na]⁺=396.39.

5B. Synthesis of Linear Tripeptides

The linear peptide of the present example was prepared via the procedureset forth in Example 4 (II) with the proline derivative prepared in step5A, D-β-vinyl cyclopropane amino acid ethyl ester, andBoc-2-amino-8-nonenoic acid.

[M+H]⁺=728.41

5C. Ring Closing Metathesis

The macrocyclic peptide ethyl ester of the present example was preparedwith the linear peptide of Step 5B via the procedure set forth inExample 4 (III).

[M+Na]⁺=722.37.

5D. Hydrolysis of the Ethyl Ester

The title compound was ultimately obtained via hydrolyisis described inExample 4 (IV) from the ethyl ester of Step 5C.

[M+H]⁺=672.49.

Example 6 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-bromophenyl, j=3, m=s=1, and R³═R⁴═H

6A. Proline Derivative Synthesis

The proline derivative of the present example was prepared by theprocedure set forth in Example 4 (I) with 5-(3-bromophenyl)-1H-tetrazoleand N-Boc-cis-hydroxyproline methyl ester 4a.

[M+Na]⁺=396.39.

6B. Synthesis of Linear Tripeptides

The linear peptide of the present example was prepared via the procedureset forth in Example 4 (II) with the proline derivative prepared in step6A, D-β-vinyl cyclopropane amino acid ethyl ester, andBoc-2-amino-8-nonenoic acid.

[M+H]⁺=728.41.

6C. Ring Closing Metathesis

The macrocyclic peptide ethyl ester of the present example was preparedwith the linear peptide of Step 6B via the procedure set forth inExample 4 (III).

[M+Na]⁺=722.37.

6D. Hydrolysis of the Ethyl Ester

The title compound was ultimately obtained via hydrolyisis described inExample 4 (IV) from the ethyl ester of Step 6C.

[M+H]⁺=672.49.

Example 7 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-bromophenyl, j=3, m=s=1, and R³═R⁴═H

7A. Proline Derivative Synthesis

The proline derivative of the present example was prepared by theprocedure set forth in Example 4 (I) with 5-(4-bromophenyl)-1H-tetrazoleand N-Boc-cis-hydroxyproline methyl ester 4a.

[M+Na]⁺=396.39.

7B. Synthesis of Linear Tripeptides

The linear peptide of the present example was prepared via the procedureset forth in Example 4 (II) with the proline derivative prepared in step7A, D-β-vinyl cyclopropane amino acid ethyl ester, andBoc-2-amino-8-nonenoic acid.

[[M+Na]+H]⁺=728.41.

7C. Ring Closing Metathesis

The macrocyclic peptide ethyl ester of the present example was preparedwith the linear peptide of Step 7B via the procedure set forth inExample 4 (III).

[M+Na]⁺=722.37.

7D. Hydrolysis of the Ethyl Ester

The title compound was ultimately obtained via hydrolyisis described inExample 4 (IV) from the ethyl ester of Step 7C.

[M+H]⁺=672.49.

Example 8 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=5-Bromo-2-thienyl, j=3, m=s=1, and R³═R⁴═H

8A. Proline Derivative Synthesis

The proline derivative of the present example was prepared by theprocedure set forth in Example 4 (I) with5-(5-Bromo-2-thienyl)-1H-tetrazole and N-Boc-cis-hydroxyproline methylester 4a.

[M+Na]⁺=480.23.

8B. Synthesis of Linear Tripeptides

The linear peptide of the present example was prepared via the procedureset forth in Example 4 (II) with the proline derivative prepared in step8A, D-β-vinyl cyclopropane amino acid ethyl ester, andBoc-2-amino-8-nonenoic acid.

[M−Boc+H]⁺=634.29.

8C. Ring Closing Metathesis

The macrocyclic peptide ethyl ester of the present example was preparedwith the linear peptide of Step 8B via the procedure set forth inExample 4 (III).

[M+Na]⁺=736.21.

8D. Hydrolysis of the Ethyl Ester

The title compound was ultimately obtained via hydrolysis described inExample 4 (IV) from the ethyl ester of Step 8C.

[M+H]⁺=678.22.

Example 9 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-bromo-4-pyridyl, j=3, m=s=1, and R³═R⁴═H

9A. Proline Derivative Synthesis

The proline derivative of the present example was prepared by theprocedure set forth in Example 4 (I) with5-(2-bromo-4-pyridyl)-1H-tetrazole and N-Boc-cis-hydroxyproline methylester 4a.

[M+Na]⁺=453.23.

9B. Synthesis of Linear Tripeptides

The linear peptide of the present example was prepared via the procedureset forth in Example 4 (II) with the proline derivative prepared in step9A, D-β-vinyl cyclopropane amino acid ethyl ester, andBoc-2-amino-8-nonenoic acid.

[M−Boc+H]⁺=629.31.

9C. Ring Closing Metathesis

The macrocyclic peptide ethyl ester of the present example was preparedwith the linear peptide of Step 9B via the procedure set forth inExample 4 (III).

[M+Na]⁺=723.36.

9D. Hydrolysis of the Ethyl Ester

The title compound was ultimately obtained via hydrolysis described inExample 4 (IV) from the ethyl ester of Step 9C.

[M+H]⁺=673.26.

Example 10 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-biphenyl, j=3, m=s=1, and R³═R⁴═H

To a deoxygenated solution of ethyl ester compound from Step 5C obtainedabove (40 mg), phenylboronic acid (10 mg), KF (100 mg), and Cs₂CO₃ (80mg) in 5 ml DME was added Pd(PPh₃)₄ (5 mg) in its solid form. Theresulting reaction mixture was heated in an oil bath to 90° C. andvigorously stirred for 6-12 hours. The solvent was evaporated and theresidue was purified by silica gel flash chromatography using differentratios of hexanes:EtOAc as the elution phase (9:1→5:1→3:1→1:1→2:1). Themacrocyclic bi-aryl peptide ethyl ester was then isolated as a whitepowder by evaporation of the elution solvents (31 mg, 78%) that wasdirectly subjected to hydrolysis, as previously described in Example 4(IV), and purified by HPLC.

[M+Na]⁺=692.38.

Example 11 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-biphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step6C and phenylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=692.38.

Example 12 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-biphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step7C phenylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=692.38.

Example 13 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-(3-thienyl)phenyl, i=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step6C and 3-thienylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=698.32.

Example 14 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-(p-trifluoromethoxyphenyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step6C and p-trifluoromethoxyphenylboronic acid via the procedure set forthin Example 10, followed by hydrolysis of the ethyl ester according tothe procedure of Example 4 (IV).

[M+Na]⁺=776.35.

Example 15 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-(p-cyanophenyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step6C and p-cyanophenylboronic acid via the procedure set forth in Example10, followed by hydrolysis of the ethyl ester according to the procedureof Example 4 (IV).

[M+Na]⁺=692.38.

Example 16 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-(3-thienyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step7C and 3-thienylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=698.32.

Example 17 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-(p-trifluoromethoxyphenyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step7C and p-trifluoromethoxyphenylboronic acid via the procedure set forthin Example 10, followed by hydrolysis of the ethyl ester according tothe procedure of Example 4 (IV).

[M+Na]⁺=776.35.

Example 18 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-(p-cyanophenyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step7C and p-cyanophenylboronic acid via the procedure set forth in Example10, followed by hydrolysis of the ethyl ester according to the procedureof Example 4 (IV).

[M+Na]⁺=692.38.

Example 19 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=5-phenyl-2-thienyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step8C and phenylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=698.32.

Example 20 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=5-phenyl-3-pyridyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester compound from Step9C and phenylboronic acid via the procedure set forth in Example 10,followed by hydrolysis of the ethyl ester according to the procedure ofExample 4 (IV).

[M+Na]⁺=708.30.

Example 21 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent, W is

Q=absent, Y=3-chloro-4-hydroxyphenyl, j=3, m=s=1, and R³═R⁴═H

Replacement Method

The title compound was prepared via the replacement of the mesylate 2and tetrazole 3a. The replacement method is performed by dissolving0.041 mmol of the macrocyclic peptide precursor mesylate 2 and 0.123mmol of tetrazole 3a in 3ml of DMF and adding 0.246 mmol of sodiumcarbonate (60 mg). The resulting reaction mixture is stirred at 60° C.for 4-10 hours and subsequently cooled and extracted with ethyl acetate.The organic extract was washed with water (2×30ml), and the organicsolution is concentrated in vacuo to be used in crude form forhydrolysis of the ethyl ester.

Example 22 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-hydroxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared by dissolving the title compound ofExample 4 (20 mg) in 2 mL of dioxane and 1 mL of 1 N LiOH aqueoussolution. The resulting reaction mixture was stirred at RT for 4-8hours. The reaction mixture was acidified with 5% citric acid, extractedwith 10 mL EtOAc, and washed with water 2×20 ml. The solvent wasevaporated and the residue was purified by HPLC on a YMC AQ12S11-0520WTcolumn with a 30-80% (100% acetonitrile) gradient over a 20 min period.After lyophilization, title compound was obtained as a white amorphoussolid.

[M+Na]⁺=666.24.

Example 23 Compound of Formula 11, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-bromo-4-hydroxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3b from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=712.18.

Example 24 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-methyl-4-bromophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3c from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=708.30.

Example 25 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-methyl-4-bromophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3d from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=708.30.

Example 26 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=n-propyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3e from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=582.33.

Example 27 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=n-butyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3f from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=596.36.

Example 28 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-ethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3g from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+H]+=660.92.

Example 29 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-propoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3h from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=674.29.

Example 30 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-butoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3i from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=688.32.

Example 31 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3j from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=646.92.

Example 32 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3,4-dimethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3k from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=676.38.

Example 33 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-methoxy-1-naphthyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 31 from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=697.00.

Example 34 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-phenoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3m from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=708.51.

Example 35 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=benzyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3n from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=630.35.

Example 36 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=D-phenylbenzyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and tetrazole 3o from Example 3, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=706.38.

Example 37 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chlorophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-chlorophenyl)-1H-tetrazole, followedby hydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=650.33.

Example 38 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-fluorophenyl, j=3, m=s=1, and R³═R⁴═H.

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-fluorophenyl)-1H-tetrazole, followedby hydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=634.37.

Example 39 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-methoxyphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=646.92.

Example 40 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-phenoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-phenoxyphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=708.51.

Example 41 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-benzyloxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-benzyloxyphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=722.32.

Example 42 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-trifluormethylphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-trifluormethylphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=684.32.

Example 43 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-bromophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-bromophenyl)-1H-tetrazole, followedby hydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=696.28.

Example 44 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-fluorophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-fluorophenyl)-1H-tetrazole, followedby hydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=634.36.

Example 45 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-methoxyphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=646.36.

Example 46 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-ethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-ethoxyphenyl)-1H-tetrazole, followedby hydrolysis of the ethyl ester by the procedure of Example 22.

[M+H]⁺=660.92.

Example 47 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-trifluoromethylphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-trifluoromethylphenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=684.32.

Example 48 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3,5-di(trifluoromethyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and5-(3,5-di(trifluoromethyl)phenyl)-1H-tetrazole, followed by hydrolysisof the ethyl ester by the procedure of Example 22.

[M+Na]⁺=766.32.

Example 49 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl, j=3,m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and5-(4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=695.39.

Example 50 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2,4-dichlorophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(2,4-dichlorophenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=684.27.

Example 51 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3,5-dichlorophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3,5-dichlorophenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=684.27.

Example 52 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3,4-dichlorophenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3,4-dichlorophenyl)-1H-tetrazole,followed by hydrolysis of the ethyl ester by the procedure of Example22.

[M+Na]⁺=684.27.

Example 53 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-pyridyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(2-pyridyl)-1H-tetrazole, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=617.60.

Example 54 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=2-pyridyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(2-pyridyl)-1H-tetrazole, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=617.60.

Example 55 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-pyridyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-pyridyl)-1H-tetrazole, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=645.24.

Example 56 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-pyridyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(4-pyridyl)-1H-tetrazole, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+H]⁺=595.50.

Example 57 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-methoxy-3-bromophenyl, j=3, m=s=1, and R³═R⁴═H

57A. Tetrazole Formation

The tetrazole of the present example was prepared by dissolving4-hydroxy-3-bromo-4-hydroxy-benzonitrile in DMF and adding methyl iodideand stirring at RT for 3-12 hours. The resulting reaction mixture wasdiluted with EtOAc and washed with water and brine. The resultingorganic phase was then dried over Na₂SO₄ and concentrated in vacuo toyield the 3-bromo4-methoxy-benzonitrile. This compound then was used toform the corresponding tetrazole via the method described in Example 3.

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and 5-(3-bromo-4-methoxy-phenyl)-1H-tetrazolefrom 57A, followed by hydrolysis of the ethyl ester by the procedure ofExample 22.

[M+Na]⁺=724.91.

Example 58 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=4-(methylcyclopropane)phenyl, j=3, m=s=1, and R³═R⁴═H

58A. Tetrazole Formation

The tetrazole of the present example was prepared by dissolving4-cyano-phenol in DMF and adding (bromomethyl)cyclopropane and stirringat RT for 3-12 hours. The resulting reaction mixture was diluted withEtOAc and washed with water and brine. The resulting organic phase wasthen dried over Na₂SO₄ and concentrated in vacuo to yield the4-(methylcyclopropane)benzonitrile. This compound then was used to formthe corresponding tetrazole via the method described in Example 3.

The title compound was prepared via the replacement method described inExample 21 with mesylate 2 and5-(4-(methylcyclopropane)-phenyl)-1H-tetrazole from 58A, followed byhydrolysis of the ethyl ester by the procedure of Example 22.

[M+Na]⁺=686.29.

Example 59 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-(methylcyclopropane)phenyl, j=3, m=s=1, andR³═R⁴═H

The tile compound was prepared by using ethyl ester title compound fromExample 21 without workup, adding (bromomethyl)cyclopropane, andstirring at 60° C. for 3-12 hours. The resulting reaction mixture wascooled to RT, poured into a mixture of 50:50 EtOAc:water, washed withwater, and concentrated in vacuo. The resulting crude ethyl estercompound is then hydrolyzed to the free acid by the procedure set forthin Example 22.

[M+Na]⁺=720.24.

Example 60 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the title compound of Example 21and methyl iodide according to the procedure set forth in Example 59.

[M+Na]⁺=680.23.

Example 61 Compound of Formula II, wherein A=tBOC, G+=OH, L=absent, W is

Q=absent, Y=3-chloro-4-ethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the title compound of Example 21and ethyl iodide according to the procedure set forth in Example 59.

[M+Na]⁺=694.28.

Example 62 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-bromo-4-ethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester precursor to thetitle compound of Example 23 and ethyl iodide according to the procedureset forth in Example 59.

[M+Na]⁺=740.17.

Example 63 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-(2-hydroxyethoxy)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared with the title compound from Example 21and 2-iodoethanol according to the procedure set forth in Example 59.

Example 64 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-bromo-4-(2-hydroxyethoxy)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester precursor to thetitle compound of Example 23 and 2-iodoethanol according to theprocedure set forth in Example 59.

[M+Na]⁺=754.27.

Example 65 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-(O-allyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the title compound from Example 21and 3-iodopropene according to the procedure set forth in Example 59.

[M+Na]⁺=706.24.

Example 66 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-bromo-4-(O-allyl)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester precursor to thetitle compound of Example 23 and 3-iodopropene according to theprocedure set forth in Example 59.

[M+Na]⁺=752.15.

Example 67 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-(O—CH₂SCH₃)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared with the title compound from Example 21and Cl—CH₂SCH₃ according to the procedure set forth in Example 59.

Example 68 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=3-chloro-4-(O-CH₂SCH₃)phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the ethyl ester precursor to thetitle compound of Example 23 and Cl—CH₂SCH₃ according to the procedureset forth in Example 59.

[M+Na]⁺=752.15.

Example 69 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

wherein Q′=-CH₂—, Y=

j=3, m=s=1, and R³═R⁴═H

69A. Preparation of Cyano Proline Derivative (69b)

To a solution of cis-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester 2-methyl ester (69a) (3.94 g, 16.06 mmol) in CH₂Cl₂(40 ml) at 0° C was DIEA (4.3 ml) and methanesulfonyl chloride (1.40 ml)dropwise. After addition, the mixture was stirred for 1.5 hours. Thereaction was complete as determined by TLC analysis (50% EtOAc-hexanewas used to develop the TLC). The mixture was diluted with EtOAc, washedwith sat. NaHCO₃, brine and dried (Na₂SO₄). After evaporation of thesolvents, the oil residue was used for next step without furtherpurification. [M+H]⁺=324.

The crude product from the previous step was dissolved in DMF(35 ml) andgrounded KCN (2.5 g) was added. The mixture was heated at 90° C.overnight. After cooled to room temperature, the mixture was dilutedwith EtOAc, washed with H₂O and brine, and dried over Na₂SO₄. The crudeproduct was purified by silica gel chromatography (20% EtOAc/hexane).

[M+H]⁺=255.

69B. Preparation of Tetrazolyl Proline Derivative (69c)

To a solution of nitrile 69b (669 mg, 2.63 mmol) in toluene (8 ml) wasadded NaN₃ (684 mg, 10.53 mmol) and Et₃N.HCl (1.45 g, 10.53 mmol). Themixture was heated at 115° C. for 18 hrs. The mixture was diluted withCH₂Cl₂, washed with 5% citric acid aqueous solution and dried overNa₂SO₄. Evaporation of solvent afforded the crude product 69c.Et₃Nadditive (660 mg).

[M+H]⁺=298.

69C. Preparation of the 5-Biphenylmethyl-tetrazolyl Proline (69e)

To a solution of 69c (92.8 mg, 0.31 mmol) in THF (2 ml) was added4-phenylbenzyl bromide (90.4 mg, 0.37 mmol) and K₂CO₃ (140 mg, 1.01mmol). The mixture was heated at 65° C. overnight and then diluted withEtOAc, washed with brine, dried over Na₂SO₄. After evaporation of thesolvent, the crude products was dissolved in THF-MeOH—H₂O (2 ml:1 ml:1ml) and LiOH (130 mg) was added. The mixture was stirred at roomtemperature overnight. THF and MeOH were evaporated under reducedpressure. The residue was dissolved in EtOAc, washed with 5% citric acidand dried with Na₂SO₄. Evaporation of solvent afforded the crude product69d and 69e.

[M+Boc+H]⁺=350.

69D. Preparation of the Tripeptide (69g)

To a solution of 69d and 69e (about 0.31 mmol) in DMF (2.0 ml) was addedD-β-vinyl cyclopropane amino acid ethyl ester.HCl (66 mg), DIEA (0.25ml) and HATU (164 mg), sequentially. The mixture was stirred for 1 hrand then was diluted with EtOAc, washed with brine, 5% citric acid anddried with Na₂SO4. After evaporation of solvent, the residue wasdissolved in 2 ml of CH₂Cl₂, 2 ml of 4 N HCl in dioxane was added. Themixture was stirred at room temperature for 1.5 hr. solvent wasevaporated. The residue was dissolved in EtOAc, neutralized with sat.NaHCO₃, washed with brine and dried with Na₂SO₄. After evaporation ofsolvent, the residue was dissolved in DMF (2 ml), to which P3 (120 mg),DIEA and HATU were added sequentially. The resulting mixture was stirredand monitored by TLC analysis. After the reaction was complete, themixture was diluted with EtOAc, washed with brine, 5% citric acid, sat.NaHCO₃, and brine again. The organic solution was dried with Na₂SO₄, andevaporated under vacuum to give the crude product mixture which waspurified by silica gel chromatography (30% to 50% EtOAc-Hexane).

[M+H]⁺=740.

69E. Ring-Closing Metathesis (69k).

The mixture of 69f and 69g (60 mg) was dissolved in dry CH₂Cl₂ to makethe concentration about 0.01 molar. The solution was carefully degassedwith N₂ stream for 15 min. 5% mol of Hoveyda's catalyst was added underN₂. The mixture was refluxed overnight. Solvent was evaporated. Theresidue was loaded on silica gel column and eluted with 10% EtOAc toremove the catalyst. The two regioisomers were separated by elution with30-40% EtOAc-hexane to give a less polar product 69j (37.9 mg) and morepolar product 69k (14.8 mg). The regiochemistry of 69j and 69k weredetermined by NMR analysis.

[M+H]⁺=712.

69F. Ethyl Ester Hydrolysis (69)

The ester 69h (37.9 mg) was dissolved in THF-MeOH—H₂O (2 ml:1 ml:1 ml)and LiOH (21 mg) was added. The mixture was stirred at room temperatureovernight. THF and MeOH were evaporated under reduced pressure. Theresidue was dissolved in EtOAc, washed with 5% citric acid and driedwith Na₂SO₄. Evaporation of solvent afforded the crude product. Thecrude product was purified by silica gel chromatography (5% MeOH inCH₂Cl₂) to give the title compound 69k.

[M+H]⁺=684.

Example 70 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

wherein Q′=-CH₂—, Y=

j=3, m=s=1, and R³═R⁴═H

The ester 69i (14.8 mg) was dissolved in THF-MeOH—H₂O (2 ml:1 ml:1 ml)and LiOH (21 mg) was added. The mixture was stirred at room temperatureovernight. THF and MeOH were evaporated under reduced pressure. Theresidue was dissolved in EtOAc, washed with 5% citric acid and driedwith Na₂SO₄. Evaporation of solvent afforded the crude product. Thecrude product was purified by silica gel chromatography (5% MeOH inCH₂Cl₂) to give title compound 70.

[M+H]⁺=684.

Example 71 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

71a—Amine Deprotection.

0.041 mmol of the title compound of Example 21 is dissolved in 4 ml of a4M solution of HCl in dioxane and stirred for 1 hour. The reactionresidue 69a is concentrated in vacuo.

71b—Chloroformate Reagent

The chloroformate reagent 71b is prepared by dissolving 0.045 mmol ofcyclopentanol in THF (3 ml) and adding 0.09 mmol of phosgene in toluene(20%). The resulting reaction mixture is stirred at room temperature for2 hours and the solvent is removed in vacuo. To the residue is added DCMand subsequently concentrated to dryness twice in vacuo yieldingchloroformate reagent 71b.

71c—Carbamate Formation

The title carbamate is prepared by dissolving residue 71a in 1 ml ofTHF, adding 0.045 mmol of TEA, and cooling the resulting reactionmixture to 0° C. To this 0° C. reaction mixture is added chloroformatereagent 71b in 3 ml of THF. The resulting reaction mixture is reactedfor 2 hours at 0° C., extracted with EtOAc, washed by 1M sodiumbicarbonate, water and brine, dried over MgSO₄, and concentrated invacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by procedure set forth inExample 22.

Example 72 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclobutyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 71with the title compound of Example 21 and cyclobutanol, followed byethyl ester hydrolysis by the procedure set forth in Example 22.

Example 73 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclohexyl, G=OH, L=absent W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 71with the title compound of Example 21 and cyclohexanol, followed byethyl ester hydrolysis by the procedure set forth in Example 22.

Example 74 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 71with the title compound of Example 21 and (R)-3-hydroxytetrahydrofuran,followed by ethyl ester hydrolysis by the procedure set forth in Example22.

Example 75 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 71with the title compound of Example 21 and (S)-3-hydroxytetrahydrofuran,followed by ethyl ester hydrolysis by the procedure set forth in Example22.

Example 76 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 71with the title compound of Example 21 and

followed by ethyl ester hydrolysis by the procedure set forth in Example22.

Example 77 Compound of Formula II, wherein A=-(C═O)—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 21 in 4 ml of a 4M solution of HCl in dioxane andstirring the reaction mixture for 1 hour. The reaction residue isconcentrated in vacuo. To this residue, 4 ml of THF and 0.045 mmol ofTEA is added, the mixture is cooled to 0° C., to which is added 0.045mmol of the cyclopental acid chloride. The resulting reaction mixture isstirred for 2 hours at 0° C. The reaction mixture is then extracted withEtOAc, washed with 1M sodium bicarbonate, water and brine, dried overMgSO₄ and concentrated to dryness in vacuo. The crude compound ispurified by silica column and the ethyl ester is subsequently hydrolyzedby the procedure set forth in Example 22.

Example 78 Compound of Formula II, wherein A=-(C═O)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 21 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. The resulting reaction residue is concentrated invacuo, dissolved in 4 ml THF, and cooled to 0° C. To the 0° C. solutionis added 0.045 mmol of cyclopentyl isocyanate and the resulting reactionmixture is stirred at RT for 4 hours. The solution is then extractedwith EtOAc, washed with 1% HCl, water and brine, dried over MgSO₄, andconcentrated in vacuo to dryness. The crude compound is purified bysilica column and the ethyl ester is subsequently hydrolyzed by theprocedure set forth in Example 22.

Example 79 Compound of Formula II, wherein A=-(C═S)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 21 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. The resulting reaction residue is concentrated invacuo, dissolved in 4 ml THF, and cooled to 0° C. To the 0° C. solutionis added 0.045 mmol of cyclopentyl isothiocyanate and the resultingreaction mixture is stirred at RT for 4 hours. The solution is thenextracted with EtOAc, washed with 1% HCl, water and brine, dried overMgSO₄, and concentrated in vacuo to dryness. The crude compound ispurified by silica column and the ethyl ester is subsequently hydrolyzedby the procedure set forth in Example 22.

Example 80 Compound of Formula II, wherein A=-S(O)₂—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 21 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. To the resulting concentrated reaction residue,which has been dissolved in 4 ml THF, is added 0.045 mmol of TEA, andcooled to 0° C. To the 0° C. solution is added 0.045 mmol of cyclopentylsolfonyl chloride and the resulting reaction mixture is stirred at 0° C.for 2 hours. The solution is then extracted with EtOAc, washed with 1Msodium bicarbonate, water and brine, dried over MgSO₄, and concentratedin vacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 22.

Example 81 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-O-phenethyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 71 and phenethyl alcohol 81a in 0.5 ml DCM, is added1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAP at 0° C. Theresulting reaction mixture is stirred for 1 hour at 0° C. and thenwarmed to RT over a period of 4-12 hours. The reaction mixture ispurified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound isolated phenethyl ester 81 b.

Other esters can be made using the same procedure.

Example 82 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NH-phenethyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 71 and phenethylamine 82a (0.05 ml) in 0.5 ml DMF,EDC (1.2 eq.) and DIEA (4 eq.) at 0° C. The resulting reaction mixtureis stirred at 1 hour. Subsequently, the reaction is warmed to RT over aperiod of 4-12 hours. The reaction mixture is purified by silica gelflash chromatography using different ratios of hexanes:EtOAc as elutionphase (9:1→5:1→3:1→1:1) to afford title compound phenethyl amide 82b.Other amides can be made using the same procedure.

Example 83 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NHS(O)₂-phenethyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 71 and α-toluenesulfonamide 83a (10 mg) in 0.5 mlDCM, is added 1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAPat 0° C. The resulting reaction mixture is stirred for 1 hour and thenallowed to warm to RT over a period of 4-12 hours. The reaction mixtureis purified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound sulfonamide 83c.

Other sulfonamides can be made using the same procedure.

Example 84 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—OH, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by adding to a solution of the titlecompound of Example 71 in 0.5 ml THF, is addedα-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA at 0°C. The resulting reaction mixture is warmed from 0° C. to RT over aperiod of 4-12 h followed by hydrolysis with concentrated hydrochloricacid in dioxane. The reaction is then extracted with EtOAc, and washedwith water and brine to yield α-hydroxy compound 83a in its crude form.The crude compound 84a undergoes a Dess-Martin oxidation in THF (0.5ml), providing the α-carbonyl compound 84b in crude form. The crude 84bis purified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound isolated keto acid 84b.

Example 85 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—O-phenethyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 84 and phenethanol according to the procedure set forth inExample 81.

Example 86 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH-phenethyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 84 and phenethyl amine according to the procedure set forth inExample 82.

Example 87 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH—S(O)₂-benzyl, L=absent, W is

Q=absent, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 84 and α-toluenesulfonamide according to the procedure set forthin Example 83.

Example 88 Compound of Formula II, wherein A=tBOC, G=OH, L=-(C═O)CH₂—, Wis

Q=absent, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

Synthesis of (2S)—N-Boc-amino-5-oxo-non-8-enoic acid

88A. The aforementioned amino acid is prepared by adding to a solutionof monoallyl ester of malonic acid in dry THF under N₂ at −78° C.,n-Bu₂Mg dropwise over a period of 5 min. The resulting suspension isthen stirred at RT for 1 hour and evaporated to dryness. Solid Mg salt88b, is dried under vacuum.

Glutamic acid derivative 88a is first mixed with1,1′-carbonyldiimidazole in anhydrous THF and the mixture is stirred atRT for 1 h to activate the free acid moiety. Subsequently, the activatedglutamic acid derivative is cannulated into a solution of Mg salt 88band the reaction mixture obtained is stirred at RT for 16 h. The mixturethen is diluted with ethyl acetate and the organic solution is washedwith 0.5 N HCl (at 0° C.) and brine, dried and evaporated. The residueobtained is resolved via silica chromatography with a 35-40% ethylacetate in hexanes eluent system to yield diester 88c.

88B. To a stirred solution of tetrakis (triphenylphosphine) PD (0) indry DMF is added the diester in DMF. The mixture is stirred at RT for3.5 hours. The DMF is evaporated under reduced pressure and the residuediluted with EtOAc. The EtOAc solution is washed with 0.5N 0° C. HCl,brine, dried and evaporated. The residue is chromatographed on silicagel using 15% to 20% EtOAc in hexane as eluent to afford the methylester intermediate.

The methyl ester intermediate is then diluted with THF and water,LiOH.H₂O is added and the resulting mixture is stirred at RT for 25hours, wherein the completion of the hydrolysis is monitored by TLC. Thereaction mixture is concentrated under vacuum to remove a majority ofthe THF and further diluted with methylene chloride. The resultingsolution is washed with 1 N HCl, dried with anhydrous Na₂SO₄ andconcentrated under vacuum. To remove minor impurities and excess Boc₂O,the crude product is purified via flash chromatography using a solventgradient from 100% hexane→100% EtOAc as the eluent.(2S)—N-Boc-amino-5-oxo-non-8-enoic acid 88d is obtained. For furtherdetails of the preceding amino acid synthesis may be found in T. Tsudaet al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929, whichare herein incorporated by reference in their entirety.

88C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using(2S)—N-Boc-amino-5-oxo-non-8-enoic acid 88d in place ofBoc-L-2-amino-8-nonenoic acid 1a followed by conversion to thecorresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 88C and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 89 Compound of Formula II, wherein A=tBOC, G=OH, L=-CH(CH₃)CH₂—,W is

Q=absent, Y=phenyl, j=1, m=s=1, R³=methyl, and R⁴═H

89A. To solid ethyl 2-acetamidomalonate 89b is added (R)-(+)-citronellal89a in a solution of pyridine over 1 min. The resulting solution iscooled in a 10° C. bath and acetic anhydride is added over 4 min. Theresulting solution is stirred for 3 h at RT and another portion of ethyl2-acetamidomalonate 89a is added. The resulting mixture is stirred at RTfor an additional 11 hours. Ice is then added and the solution isstirred for 1.5 hours, then the mixture is diluted with 250 ml water andextracted with two portions of wther. The organic phase is washed with1N HCl, sat. NaHCO₃, dried Na₂SO₄, concentrated and purified by flashchromatography (40% EtOAc/hexane) to afford compound 89c.

89B. To a degassed solution of 89c in dry ethanol is added(S,S)-Et-PUPHOS Rh(COD)OTf. The mixture is subjected to 30 psi ofhydrogen and stirred on a Parr shaker for 2 hours. The resulting mixtureis evaporated to dryness to obtain the crude compound 50d, which is usedin the subsequent step without purification.

89C. Compound 89d is dissolved in a mixture of tBuOH/acetone/H₂O (1:1:1)and placed in an ice bath (0° C. ). NMMO and OSO₄ is consecutively addedand the reaction mixture is stirred at RT for 4 hours. A majority of theacetone is removed by evaporation under vacuum and then the mixture isextracted with ethyl acetate. The organic layer is further washed withwater and brine, dried over anhydrous MgSO₄ and evaporated to dryness.The diol 50e is obtained in high purity after flash columnchromatography using 1% ethanol in ethyl acetate as the eluent.

89D. To a solution of diol 89e in THF/H₂O (1:1) at 0°°C., NalO₄ is addedand the reaction mixture is stirred at RT for 3.5 hours. A majority ofthe THF solvent is subsequently removed by evaporation under vacuum andthe remaining mixture is extracted with EtOAc. The combined organiclayers is further washed with 5% aqueous citric acid solution, 5% aq.NaHCO₃ and brine, then the organic phase is dried over MgSO₄ andevaporated to dryness under vacuum. Aldehyde intermediate 89f is used inthe following step in its crude form.

89E. To a solution of Ph₃PCH₃Br in anhydrous toluene, KHMDS is addedforming a suspension which is stirred at RT for 30 min. under N₂. Afterstirring, the suspension is cooled to 0° C., a solution of aldehydeintermediate 89f in THF is added, the mixture is warmed to RT, andstirred for 1 hour. A majority of the THF is evaporated under vacuum,EtOAc is added to the mixture and the organic phase is washed withwater, 5% aq. NaHCO₃ and brine. The organic phase is then dried overMgSO₄ and evaporated to dryness under vacuum. Pure compound 89g isisolated after purification via flash chromatography on silica gel,using hexane:EtOAc (3:2) as the eluent.

89F. To a solution of crude 89g in THF, Boc₂O, and DMAP is added and thereaction mixture is heated to reflux for 2.5 hours. Subsequently, amajority of the THF is evaporated, the crude mixture is diluted withmethylene chloride and washed with 1 N HCl to remove DMAP. The organiclayer is further extracted with saturated aq. NaHCO₃, dried withanyhrous Na₂SO₄ and concentrated under vacuum. The crude product is thendiluted with THF and water, LiOH.H₂Ois added and the resulting mixtureis stirred at RT for 25 hours, wherein the completion of the hydrolysisis monitored by TLC. The reaction mixture is concentrated under vacuumto remove a majority of the THF and further diluted with methylenechloride. The resulting solution is washed with 1 N HCl, dried withanhydrous Na₂SO₄ and concentrated under vacuum. To remove minorimpurities and excess Boc₂O, the crude product is purified via flashchromatography using a solvent gradient from 100% hexane→100% EtOAc asthe eluent. (2S, 5R)—N-Boc-2-amino-5-methyl-non-8-enoic acid 89h isobtained. For further details of the preceding amino acid synthesis seeWO 00/59929, which is herein incorporated by reference in its entirety.

89G. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using ((2S,5R)—N-Boc-2-amino-5-methyl-non-8-enoic acid 89h in place ofBoc-L-2-amino-8-nonenoic acid 1a followed by conversion to thecorresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 89G and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 90 Compound of Formula II, wherein A=tBOC, G=OH, L=-O—, W is

Q=absent, Y=phenyl, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

90A. Boc-(L)-threonine 90a is partially dissolved in methylenechloride/methanol at 0° C. A solution of diazomethane in diethyl etheris added until yellow, indicating the presence of diazomethane. Uponevaporation of the solvents, crude methyl ester 90b is obtained.

90B. Intermediate 90b is dissolved in anhydrous diethyl ether, Ag₂O isadded and freshly activated 4 Å molecular sieves. Finally, allyl iodideis added to the reaction mixture and is stirred at reflux. Twoadditional portions of allyl iodide are added to the reaction mixtureafter a period of 20 hours and 30 hours and stirring is continued for atotal of 36 hours. The mixture is then filtered through celite andpurified by flash chromatography on silica gel, using EtOAc/hexane (1:4)as the eluent, to afford compound 90c.

90C. Compound 90c is dissolved in a mixture of THF/MeOH/H₂O (2:1:1) andLiOH.H₂O is added. The solution is stirred at RT for 2 h, and the isacidified with 1 N HCl to pH ˜3 before the solvents are removed undervacuum. The resulting crude compound 90d is obtained. For furtherdetails of the preceding amino acid synthesis see WO 00/59929, which isherein incorporated by reference in its entirety.

90D. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using N-Boc-O-allyl-(L)-threonine90d in place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversionto the corresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 90D and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 91 Compound of Formula II, wherein A=tBOC, G=OH, L=-S—, W is

Q=absent, Y=phenyl, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

Synthesis of (2S, 3S)-N-Boc-2amino-3(mercaptoallyl)butanoic acid (91e)

91A. Compound 91a is dissolved in pyridine and the solution is cooled to0° C. in an ice bath, tosyl chloride is added in small portions and thereaction mixture is partitioned between diethyl ether and H₂O. The etherlayer is further washed with 0.2 N HCl and brine, dried over anhydrousMgSO₄, filtered and concentrated to dryness under vacuum. Purificationof the crude material by flash chromatography on silica gel, usinghexane/EtOAc (gradient from 8:2 to 7:3 ratio) as the eluent, led toisolation of tosyl derivative 91b.

91B. To a solution of tosyl derivative 91b in anhydrous DMF, potassiumthioacetate is added and the reaction mixture is stirred at RT for 24hours. A majority of the DMF is then evaporated under vacuum and theremaining mixture is partitioned between EtOAc and H₂O. The aqueouslayer is re-extracted with EtOAc, the combined organic layers are washedwith brine, dried over anhydrous MgSO₄ and evaporated to dryness.Purification of the crude material by flash chromatography on silica gelusing hexane/EtOAc (4:1 ratio) as the eluent, affords thioester 91c.

91C. To a solution of thioester 91c is H₂O/EtOH (3:5 ratio) and aqueoussolution of 0.2M NaOH is added and the mixture is stirred at RT for 1.5hours. Allyl iodide is then added and stirring is continued at RT for anadditional 30 min. The reaction mixture is concentrated to half of itsoriginal volume and then extracted with EtOAc. The aqueous layer isacidified to pH ˜3 with cold, aqueous 0.5N HCl and re-extracted withEtOAc. The combined organic layers are washed with brine, dried overanhydrous MgSO₄ and evaporated to dryness under vacuum. The crudereaction mixture contains at least four products; all of the productsare isolated after flash chromatography on silica gel, usinghexane/EtOAc (gradient from 9:1 to 3:1). The desired product 91d is theleast polar compound.

91D. A solution of compound 91d in MeOH/H₂O (3:1) is mixed with aqueousNaOH (0.3 N) for 24 hours at RT and for 1 hour at 40° C. The reactionmixture is acidified with cold aqueous 0.5 N HCl, the MeOH is removedunder vacuum and the remaining aqueous mixture is extracted with EtOAc.The organic phase is dried over MgSO₄ and evaporated to dryness in orderto obtain compound 91e. For further details of the preceding amino acidsynthesis see WO 00/59929, which is herein incorporated by reference inits entirety.

91 E. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using (2S, 3S)-N-Boc-2amino-3(mercaptoallyl)butanoic acid 52e in place ofBoc-L-2-amino-8-nonenoic acid 1a followed by conversion to thecorresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 91 E and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 92 Compound of Formula II, wherein A=tBOC, G=OH, L=-S(O)—, W is

Q=absent, Y=phenyl, j=2, m=s=1, R³=methyl and R⁴=hydrogen

Formation of Modified Amino Acid

92A. The modified amino acid is prepared by dissolving sodiummetaperiodate (1.1 eq.) in water and cooled to 0° C. in an ice bathfollowed by adding dropwise a solution of compound 91d in dioxane. Theresulting reaction mixture is stirred for one hour at 0° C. and 4 hoursat 40° C. The reaction mixture is concentrated, water is added, and themixture is extracted with methylene chloride twice. The combined organiclayers are washed with water, brine, dried with anhydrous MgSO₄ andconcentrated in vacuo. The methyl ester is then reduced via the methodset forth in Example 91D to arrive upon the modified amino acid 92a. Forfurther details of the preceding amino acid synthesis may be found in T.Tsuda et al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929,which are herein incorporated by reference in their entirety.

92B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using the modified amino acid 92ain place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion tothe corresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 92B and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 93 Compound of Formula II, wherein A=tBOC, G=OH, L=-S(O)₂—, W is

Q=absent, Y=phenyl, j=2, m=s=1, R³=methyl, and R⁴═H

Formation of Modified Amino Acid

93A. The modified amino acid is prepared by dissolving sodiummetaperiodate (1.1 eq.) in water and cooled to 0° C. in an ice bathfollowed by adding dropwise a solution of compound 92d in dioxane. Theresulting reaction mixture is stirred for one hour at 0° C. and 4 hoursat 40° C. The reaction mixture is concentrated, water is added, and themixture is extracted with methylene chloride twice. The combined organiclayers are washed with water, brine, dried with anhydrous MgSO₄ andconcentrated in vacuo. The methyl ester is then reduced via the methodset forth in Example 91D to arrive upon the modified amino acid 92a. Forfurther details of the preceding amino acid synthesis may be found in T.Tsuda et al., J. Am. Chem. Soc., 1980, 102, 6381-6384 and WO 00/59929,which are herein incorporated by reference in their entirety.

93B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using the modified amino acid 93ain place of Boc-L-2-amino-8-nonenoic acid la followed by conversion tothe corresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 93B and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 94 Compound of Formula II, wherein A=tBOC, G=OH, L=-SCH₂CH₂—, Wis

Q=absent, Y=phenyl, j=0. m=s=1, and R³═R⁴═CH₃

94A. Synthesis of(S)-N-Boc-2-amino-3-methyl-3(1-mercapto-4-butenyl)butanoic acid (94b)

L-Penicillamine 94a is dissolved in DMF/DMSO (5:1), subsequently,4-bromopentene and CsOH.H₂O are added to the mixture and stirring iscontinued for an additional 12 hours. The DMF is subsequently removed invacuo, the remaining mixture is diluted with 0.5 N HCl (at 0° C.) toadjust the pH to ˜4-5 and then extracted with 2 portions of EtOAc. Theorganic phase is washed with brine (2×), dried over MgSO₄ and evaporatedto dryness to afford the crude carboxylic acid 94a. For further detailsof the preceding amino acid synthesis see WO 00/59929, which is hereinincorporated by reference in its entirety.

94B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using the modified amino acid 94ain place of Boc-L-2-amino-8-nonenoic acid la followed by conversion tothe corresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 94B and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 95 Compound of Formula II, wherein A=tBOC, G=OH, L=-CF₂CH₂—, Wis

Q=absent, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

95A. To a solution of the ketone compound 88d (0.30 g, 1 mmol) in 5 mlDCM, DAST (Diethylaminosulfurtrifluoride, 0.2 g, 1.2 eq) is added. Thereaction is kept at RT over a period of 2-3 days. The solvent isevaporated and the residue is purified by silica gel flashchromatography using different ratios of hexanes:EtOAc as eluent(9:1→5:1→3:1→1:1), providing the isolated methyl ester 95a. For furtherdetails concerning the preceding synthesis, see Tius, Marcus A et al.,Tetrahedron, 1993, 49, 16; 3291-3304, which is herein incorporated byreference in its entirety.

95B. Methyl ester 95a is dissolved in THF/MeOH/H₂O (2:1:1) and LiOH.H₂Ois added. The solution is stirred at RT for 2hours, and is thenacidifies with 1 N HCl to pH ˜3 before the solvents are removed in vacuoto afford the crude (2S)—N-Boc-amino-5-difluoro-non-8-enoic acid 95b.

95C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using crude(2S)—N-Boc-amino-5-difluoro-non-8-enoic acid 95b in place ofBoc-L-2-amino-8-nonenoic acid la followed by conversion to thecorresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 95C and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 96 Compound of Formula II, wherein A=tBOC, G=OH, L=-CFHCH₂—, Wis

Q=absent, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

96A. To a solution of the ketone compound 88d in 5 ml methanol, NaBH₄(2.2 eq) is added. The reaction mixture is stirred at RT over a periodof 2-6 hours, and then quenched by 1M ammonium chloride and extractedwith EtOAc (30 ml). The solvent is evaporated and the crude hydroxycompound 96a is obtained.

96B. The hydroxy compound 96a is dissolved in 5 ml DCM to which DAST(0.2 g, 1.2 eq) is added and stirred at −45° C. for 1 hour. The reactionmixture is then warmed to RT and stirred over a period of 2-3 days. Thesolvent is evaporated and the residue is purified by silica gel flashchromatography using different ratios of hexanes:EtOAc as eluent(9:1→5:1→3:1→1:1), providing the isolated monofluoro compound methylester 95b. For further details concerning this synthesis see Buist,Peter H et al., Tetrahedron Lett., 1987, 28, 3891-3894, which is hereinincorporated by reference in its entirety.

96B. Methyl ester 96b is dissolved in THF/MeOH/H₂O (2:1:1) and LiOH.H₂Ois added. The solution is stirred at RT for 2 hours, and is thenacidifies with 1 N HCl to pH ˜3 before the solvents are removed in vacuoto afford the crude (2S)-N-Boc-amino-5-difluoro-non-8-enoic acid 96c.

96C. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using crude(2S)-N-Boc-amino-5-monofluoro-non-8-enoic acid 96b in place ofBoc-L-2-amino-8-nonenoic acid 1a followed by conversion to thecorresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 96C and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

Example 97 Compound of Formula III, wherein A=tBOC, G=OH, L=absent, W is

Q=absent, Y=Phenyl, j=3, m=s=1, and R³═R⁴═H

97A. The saturated cyclic peptide precursor mesylate is prepared bycatalytic reduction of the mesylate cyclic peptide precursor 2 with Pd/Cin MeOH in the presence of H₂.

The title compound is prepared with the saturated cyclic peptideprecursor mesylate formed in 97A and 5-phenyl-1H-tetrazole by thereplacement method elucidated in Example 21 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 22.

The compounds of the present invention exhibit potent inhibitoryproperties against the HCV NS3 protease. The following exampleselucidate assays in which the compounds of the present invention weretested for anti-HCV effects.

Example 98 Triazole Synthesis

Exemplary triazole derivatives for use in preparing compounds of theinvention may be prepared as set forth in the examples below:

Triazoles of the present invention may be prepared by reacting 4 mmol ofalkyne compound 98a, which is commercially available or made fromprocedures elucidated infra, and 8 mmol of trimethylsilyl azide in 2 mlof xylenes in a pressure tube for 24-72 hours at 140° C. The resultingreaction mixture was directly separated by silica column, yieldingtriazole 98b in 30-90% yield.

Example 99 Alykyne Synthesis

Alkynes used in the present invention can be made by the Sonogashirareaction by reaction of a degassed solution of 4 mmol of primary alkynecompound 99a, 4 mmol of an aryl halide (Y-halide), and 1 ml oftriethylamine and 10 ml of acetonitrile with 140 mg(0.2 mmol) ofPdCl₂(PPh₃)₂ and 19 mg(0.1 mmol) of Cul. The resulting reaction mixtureis degassed and stirred for 5 minutes at RT. The reaction is then heatedto 90° C. and stirred for 12 hours. Subsequently, the reaction mixtureis concentrated in vacuo and purified by silica column to afford thesubstituted alkyne 98a in a 60-90% yield.

Additional alkynes used in the present invention can be made by reacting10 mmol of alkynyl acid 99b, 11 mmol of BOP, and 22 mmol of DIEA in 15ml of DMF with 11 mmol of amine 99b and stirring at room temperature for3 hours. The reaction mixture is then extracted by ethyl acetate (2×50ml); washed with 1M NaHCO3(2×30 ml), water(2×30 ml), 5% citric acid(2×50ml) and brine(2×30 ml); dried over anhydrous sodium sulfate; andconcentrated in vacuo to afford alkyne 99d in a 90% yield.

Example 100 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X═H, Y=4-t-butylphenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared by the following method: 2 mmol (0.54 g)of Boc methyl ester azidoproline 100a and 2.5mmol of4-tert-Butylphenylacetylene 100b were dissolved in 2 ml of xylenes andstirred at 110° C. for 12 hours. The resulting reaction mixture wasdirectly separated by silica column to resolve isomers 100c and 100d,with a yield of 90%.

The title compound was then formed via the RCM procedure described inExample 1 using 100b in the place of hydroxyl proline, followed byhydrolysis of the ethyl ester via the procedure described in Example106.

[M+Na]⁺=671.72.

Example 101 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=4-t-butylphenyl, Y═H, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared via RCM procedure described in Example 1using 100c in the place of hydroxyl proline, followed by hydrolysis ofthe ethyl ester via the procedure described in Example 106.

[M+H]⁺=649.44.

Example 102 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X and Y are taken together=phenyl, j=3, m=s=1, and R³═R⁴═H

The triazole-substituted proline corresponding to the title compound wasprepared by dissolving 1.5 mmol(0.5 g) of hydroxyproline mesylate 102aand 4.5 mmol of benzotriazole 102b in 5 ml of DMF, adding 9 mmol(2.9 g)of cesium carbonate and stirring the resulting reaction mixture at 70°C. for 12 hours. The reaction mixture was extracted with EtOAc, washedwith 1M sodium bicarbonate and brine. The organic layer was dried overMgSO₄ and concentrated in vacuo. Expected isomers 102c and 102d wereresolved via silica column chromatography.

The title compound was then formed via the RCM procedure described inExample 1 using 102d in the place of hydroxyl proline, followed byhydrolysis of the ethyl ester via the procedure described in Example106.

[M+Na]⁺=588.46.

Example 103 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X and Y taken together=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was formed via the RCM procedure described in Example1 using 102c in the place of hydroxyl proline, followed by hydrolysis ofthe ethyl ester via the procedure described in Example 106.

[M+Na]⁺=588.50.

Example 104 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The triazole-substituted proline corresponding to the title compound wasprepared by dissolving 1.5 mmol(0.5 g) of hydroxyproline mesylate 102aand 4.5 mmol of benzotriazole 102b in 5 ml of DMF, adding 9 mmol(2.9 g)of cesium carbonate and stirring the resulting reaction mixture at 70°C. for 12 hours. The reaction mixture was extracted with EtOAc, washedwith 1M sodium bicarbonate and brine. The organic layer was dried overMgSO₄ and concentrated in vacuo.

The title compound was then formed via the RCM procedure described inExample 1 using the triazole-substituted proline of the present examplein the place of hydroxyl proline, followed by hydrolysis of the ethylester via the procedure described in Example 106.

[M+Na]⁺=690.42.

Example 105 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent, Wis

X=Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared by dissolving 0.041 mmol of the titlecompound of Example 2 and 0.123 mmol of 4,5-diphenyltriazole in 3 ml ofDMF, adding 0.246 mmol of cesium carbonate (80 mg), and reacting at 70°C. for 12 hours. The reaction mixture was then extracted with EtOAc andwashed with 1M sodium bicarbonate (2×30 ml) and water (2×30 ml). Theresulting organic solution was concentrated in vacuo to dryness.

Example 106 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X═Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared by dissolving 0.041 mmol of the titlecompound of Example 105 in 3 ml of dioxane, adding 2 ml of 1M LiOH, andreacting at RT for 8 hours. Subsequently, the pH of reaction mixture wasadjusted to 3 with citric acid, extracted with EtOAc, followed bywashing with brine and water. The organic solution was concentrated invacuo for purification by HPLC.

[M+Na]⁺=690.42.

Example 107 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X═Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The triazole-substituted proline precursor of the title compound wasprepared by dissolving 0.93 mmol (0.25 g) of azidoproline 100a and 1mmol of diphenyl acetylene in 2 ml of xylenes, heated to 110° C., andstirred for 12 hours. The reaction mixture was directly separated bysilica column to afford 0.27 g of 107a (90%). [M+H]+: 449.05. 0.26 g of107b was obtained by the hydrolysis procedure elucidated in Example 105(99%).

The title compound was then formed via the RCM procedure described inExample 1 using 107b in the place of hydroxyl proline.

[M+Na]⁺=691.99.

Example 108 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=n-propyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

108a Triazole Formation

The 4-(n-propyl)-5-phenyltriazole was prepared via the procedure ofExample 98 using n-propyl phenylacetylene and sodium azide.

The title compound was prepared with the title compound of Example 2 and4-(n-propyl)-5-phenyltriazole 108a according to the procedure set forthin Example 105 and subsequent hydrolysis of the ethyl ester via theprocedure of Example 106.

[M+Na]⁺=657.99.

Example 109 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=m-methoxyphenyl Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

109a Alkyne Formation

The 2-(m-methoxyphenyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 4-methoxyphenylacetylene and3-bromoanisole.

109b Triazole Formation

The 4-(m-methoxyphenyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using alkyne 109a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(m-methoxyphenyl)-5-(p-methoxyphenyl)triazole 109a according tothe procedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+Na]⁺=752.08.

Example 110 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=m-bromophenyl Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

110a Alkyne Formation

The 2-(m-bromophenyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 4-methoxyphenylacetylene and3-iodo-5-bromobenzene.

110b Triazole Formation

The 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using alkyne 110a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole 110a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+Na]⁺=800.05.

Example 111 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=1-napthyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

111a Alkyne Formation

The 2-(1-napthyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 1-iodonapthelene and4-methoxyphenylacetylene.

111 b Triazole Formation

The 4-(m-bromophenyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(1-napthyl)-4-methoxyphenylacetylene 113aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(1-napthyl)-5-(p-methoxyphenyl)triazole 113a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+Na]⁺=772.11.

Example 112 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=2-thienyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

112a Alkyne Formation

The 2-(2-thienyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 2-iodo-thiophene and4-methoxyphenylacetylene.

112b Triazole Formation

The 4-(2-thienyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(2-thienyl)-4-methoxyphenylacetylene 112aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(2-thienyl)-5-(p-methoxyphenyl)triazole 112a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=705.31.

Example 113 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=3-thienyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

113a Alkyne Formation

The 2-(3-thienyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99a from 2-iodo-thiophene and4-methoxyphenylacetylene.

113b Triazole Formation

The 4-(3-thienyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(3-thienyl)-4-methoxyphenylacetylene 113aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(3-thienyl)-5-(p-methoxyphenyl)triazole 113a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+Na]⁺=727.21.

Example 114 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=4-pyrazolyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

114a Alkyne Formation

The 2-(4-pyrazolyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 4-iodopyrazole and4-methoxyphenylacetylene.

114b Triazole Formation

The 4-(4-pyrazolyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(4-pyrazolyl)-4-methoxyphenylacetylene114a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(4-pyrazolyl)-5-(p-methoxyphenyl)triazole 114a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=700.82.

Example 115 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=3-pyridyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

115a Alkyne Formation

The 2-(3-pyridyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 3-iodopyridine and4-methoxyphenylacetylene.

115b Triazole Formation

The 4-(3-pyridyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(3-pyridyl)-4-methoxyphenylacetylene 115aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(3-pyridyl)-5-(p-methoxyphenyl)triazole 115a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=700.36.

Example 116 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=2-pyridyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

116a Alkyne Formation

The 2-(2-pyridyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99A from 2-iodopyridine and4-methoxyphenylacetylene.

116b Triazole Formation

The 4-(2-pyridyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(2-pyridyl)-4-methoxyphenylacetylene 116aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(2-pyridyl)-5-(p-methoxyphenyl)triazole 116a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=700.82.

Example 117 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=2-thiazolyl, Y=p-methoxyphenyl, j=3, m=s=1, and R³═R⁴═H

117A. Alkyne Formation

The alkyne of the current example,2-(2-thiazolyl)-4-methoxyphenylacetylene was prepared by adding to adegassed solution of 4 mmol of 4-ethynylanisole, 4 mmol of2-bromothiazole, and 1 ml of triethylamine in 10 ml of acetonitrile,140mg(0.2 mmol) of PdCl₂(PPh₃)₂ and 19 mg(0.1 mmol) of Cul. The mixture wasdegassed and stirred for 5 minutes at RT and heated to 90° C. for 12hours. The reaction mixture was concentrated in vacuo and purified bysilica column to afford 0.61 g of brown liquid in a 70% yield.

[M+H]+: 216.17, 1HNMR (CDCl₃, 500 MHz) δ 7.765(d, J=3 Hz, 1H),7.472˜7.455(m, 2H), 7.277 (d, J=3.5 Hz, 1H), 6.837˜6.820 (m, 2H), 3.768(s, 3H).

117B. Triazole Formation

The 4-(2-thiazolyl)-5-(p-methoxyphenyl) triazole 117d was prepared byadding to a pressure tube 0.3 g of 117c, 0.74 ml of trimethylsilylazide, and 4ml of xylenes and heating the mixture to 140° C. for 48hours. The reaction mixture was directly separated by silica column toafford a brown liquid (117d) after purification (0.18 g, 50%).

[M+H]+: 259.27, 1HNMR (DMSO-d₆), 500 MHz) δ 8.016(d, J=8.5 Hz, 2H),7.929(d, J=3 Hz, 1H), 7.817(d, J=3 Hz, 1H), 7.066(d, J=8.5 Hz, 2H),3.824(s, 3H).

117c. Ethyl Ester 117e was prepared by dissolving 0.041 mmol of mesylateof macrocyclic precursor 117d and 0.123 mmol of 117d in 3 ml of DMF,adding 0.246 mmol cesium carbonate, and reacting at 70° C. for 12 hours.The reaction mixture was extracted with EtOAc, washed with 1 M sodiumbicarbonate (2×30 ml) and water (2×30 ml), and concentrated in vacuo toobtain ethyl ester 117e.

[M+H]+: 734.34

Preparation of Title Compound

Hydrolysis of ethyl ester 117c was achieved by dissolving 117e in 3 mlof dioxane, adding 2 ml of 1M LiOH, and stirring the resulting reactionmixture at RT for 8 hours. The pH of the reaction mixture was adjustedto 3 with citric acid; then the reaction mixture was extracted withEtOAc, and washed with brine and water. The organic solution wasconcentrated in vacuo for purification by HPLC which afforded a yellowpowder after lyophilization (10 mg, yield 34%).

[M+H]+: δ6.33, 1HNMR (DMSO-d₆, 500 MHz) δ 12.283 (s, broad, 1H), 8.750(s, broad, 1H), 8.014 (d, J=9 Hz, 2H), 7.938 (d, J=3.5 Hz, 1H), 7.852(d, J=3.5 Hz, 1H), 6.997 (d, J=8 Hz, 2H), 6.927 (d, J=7, 1H), 5.555 (s,broad, 1H), 5.499 (m, 1H), 5.298 (t, J=18 Hz and 9 Hz, 1H), 4.643 (t,J=16 Hz and 8 Hz, 1H), 4.558 (d, J=11.5 Hz, 1H), 4.125˜4.093 (m, 2H),3.802 (s, 3H), 2.890˜2.847 (m, 1H), 2.542˜2.497(m, 2H), 2.123˜2.106 (m,1H), 1.806(s, broad, 1H), 1.701˜1.663(m, 1H), 1.519(s, broad, 1H),1.460˜1.435(m, 1H), 1.314˜1.074(m, 16H).

Example 118 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=benzyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

118a Alkyne Formation

The 2-(benzyl)-4-methoxyphenylacetylene was prepared via the procedureof Example 117A from 4-iodobenzene and 3-phenyl-propyne.

118b Triazole Formation

The 4-(benzyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(benzyl)-4-methoxyphenylacetylene 118aand sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(2-benzyl)-5-(p-methoxyphenyl)triazole 118a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=700.82.

Example 119 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=n-butyl, Y=phenyl, i=3, m=s=1, and R³═R⁴═H

119a Triazole Formation

The 4-(n-butyl)-5-phenyl triazole was prepared via the procedure ofExample 3 using n-butyl-1-phenylacetylene and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(n-butyl)-5-phenyl triazole 119a according to the procedure setforth in Example 105 and subsequent hydrolysis of the ethyl ester viathe procedure of Example 106.

[M+H]⁺=649.44.

Example 120 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=n-propyl, Y=n-propyl, j=3, m=s=1, and R³═R⁴═H

120a Triazole Formation

The 4,5-(n-propyl)triazole was prepared via the procedure of Example 3using 4-octyne and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4,5-(n-propyl)triazole 120a according to the procedure set forth inExample 105 and subsequent hydrolysis of the ethyl ester via theprocedure of Example 106

[M+H]⁺=601.46.

Example 121 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=4-(N,N-dimethylamino)phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

121A. Bromination. Bromo-substituted phenyl triazole 121b was preparedby dissolving 1 mmol of 121a (Triazole 121a was prepared by the methodset forth in Example 2 using commercial phenyl acetylene and sodiumazide) in 16 ml 1:15 MeOH/CHCl₃, adding 0.28 ml of TEA, and in adropwise manner adding 0.128 ml of bromine. The resulting reactionmixture was stirred for 2 hours. To the reaction mixture was added cold10% Na₂S₂O₅ until the the mixture turned colorless. The mixture wasextracted with EtOAc, washed with brine and water, dried over Na₂SO₄,and concentrated in vacuo to afford 0.216 g of 121b after purificationby silica column (97%). [M+H]+: 224.19.

121B. Mesylate replacement. 0.2 g of 121c was prepared via the procedureelucidated in Example 3 from purified 121b and the title compound fromExample 2. [M+Na]+: 721.00.

121C. Suzuki Coupling. Ethyl ester 121d was prepared by dissolving 0.07mmol (50 mg) of 121c in 3 ml of DME and adding to this solution 0.21mmol (35 mg) of 4-dimethylaminophenyl boric acid, 137 mg of cesiumcarbonate, and 100 mg of KF. To the subsequently degassed reactionmixture was added 5 mg of Pd(PPh₃)₄. The resulting reaction mixture washeated to 90° C. and stirred for 12 hours. The reaction mixture then wasextracted with EtOAc, washed with brine and water, dried over Na₂SO₄,concentrated in vacuo, and purified by silica column to afford 40 mg(78% yield) of 121d.

121D. Ethyl Ester Hydrolysis. 12 mg of 121e was made via the procedureset forth in 106 from 121d after purification by HPLC (30%).[M+H]+:712.33.

Example 122 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=(N,N-diethylamino)methyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

122a Triazole Formation

The 4-(N,N-diethylaminomethyl)-5-phenyltriazole was prepared via theprocedure of Example 3 using 3-diethylamino-1-phenylpropyne and sodiumazide.

The title compound was prepared with the title compound of Example 2 andthe 4-(N,N-diethylaminomethyl)-5-phenyltriazole 122a according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=678.44.

Example 123 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=N,N-diethylaminocarbonyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

123A. Alkyne Formation

Alkyne 123a was prepared by dissolving 10 mmol of phenylpropynoic acid,11 mmol of BOP, and 22 mmol of DIEA in 15 ml of DMF and to which wasadded 11 mmol of diethylamine. The resulting reaction mixture was thenstirred at RT for 3 hours. The reaction mixture was extracted with EtOAc(2×50 ml), washed with 1M NaHCO3 (2×30 ml), water (2×30 ml), 5% citricacid (2×50 ml), and brine (2×30 ml). The organic extract was dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford 1.8 g (90%) of 123a[M+H]+:202.09.

123B. Triazole Formation

The 4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b was prepared viathe procedure of Example 3 using 123a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(N,N-diethylaminocarbonyl)-5-phenyltriazole 123b according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]+:692.47.

Example 124 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=m-chlorophenyl, Y=4-ethoxyphenyl, j=3, m=s=1, and R³═R⁴═H

124a Alkyne Formation

The 2-(m-chlorophenyl)-4-methoxyphenylacetylene was prepared via theprocedure of Example 99 from 3-chloro-bromobenzene and4-methoxyphenylacetylene.

124b Triazole Formation

The 4-(m-chlorophenyl)-5-(p-methoxyphenyl)triazole was prepared via theprocedure of Example 3 using 2-(m-chlorophenyl)-4-methoxyphenylacetylene124a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-( m-chlorophenyl)-5-(p-methoxyphenyl)triazole 124a according tothe procedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

[M+H]⁺=747.37.

Example 125 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

X=2-phenylethenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with by the Suzuki reaction described inExample 121 from 121c and phenylethenylboronic acid and subsequenthydrolysis by the procedure described in Example 106.

[M+H]⁺=695.30.

Example 126 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is5,6-methylbenzotriazole, j=3, m=s=1, and R³═R⁴═H

The title compound was prepared with the title compound of Example 2 andthe 5,6-methylbenzotriazole according to the procedure set forth inExample 105 and subsequent hydrolysis of the ethyl ester via theprocedure of Example 106.

[M+H]⁺=595.42.

Example 127 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

L , X=N-ethylaminocarbonyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

127a. Alkyne Formation

Alkyne 127a was prepared by dissolving 10 mmol of phenylpropynoic acid,11 mmol of BOP, and 22 mmol of DIEA in 15 ml of DMF and to which wasadded 11 mmol of ethylamine. The resulting reaction mizture was thenstirred at RT for 3 hours. The reaction mixture was extracted with EtOAc(2×50 ml), washed with 1M NaHCO3 (2×30 ml), water (2×30 ml), 5% citricacid (2×50 ml), and brine (2×30 ml). The organic extract was dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford 1.8 g (90%) of127a. [M+H]+:177.09.

127b Triazole Formation

The 4-(N-ethylaminocarbonyl)-5-phenyltriazole was prepared via theprocedure of Example 3 using 127a and sodium azide.

The title compound was prepared with the title compound of Example 2 andthe 4-(N-ethylaminocarbonyl)-5-phenyltriazole 127b according to theprocedure set forth in Example 105 and subsequent hydrolysis of theethyl ester via the procedure of Example 106.

Example 128 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

128a—Amine deprotection.

0.041 mmol of the title compound of Example 105 is dissolved in 4 ml ofa 4M solution of HCl in dioxane and stirred for 1 hour. The reactionresidue 128a is concentrated in vacuo.

128b—Chloroformate Reagent

The chloroformate reagent 128b is prepared by dissolving 0.045 mmol ofcyclopentanol in THF (3 ml) and adding 0.09 mmol of phosgene in toluene(20%). The resulting reaction mixture is stirred at room temperature for2 hours and the solvent is removed in vacuo. To the residue is added DCMand subsequently concentrated to dryness twice in vacuo yieldingchloroformate reagent 128b.

128c—Carbamate Formation

The title carbamate is prepared by dissolving residue 128a in 1 ml ofTHF, adding 0.045 mmol of TEA, and cooling the resulting reactionmixture to 0° C. To this 0° C. reaction mixture is added chloroformatereagent 128b in 3 ml of THF. The resulting reaction mixture is reactedfor 2 hours at 0° C., extracted with EtOAc, washed by 1M sodiumbicarbonate, water and brine, dried over MgSO₄, and concentrated invacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 106.

Example 129 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclobutyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 33with the title compound of Example 105 and cyclobutanol, followed byethyl ester hydrolysis by the procedure set forth in Example 106.

Example 130 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclohexyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method in Example 33 with thetitle compound of Example 105 and cyclohexanol, followed by ethyl esterhydrolysis by the procedure set forth in Example 106.

Example 131 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹=

G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method described in Example 33with the title compound of Example 105 and (R)-3-hydroxytetrahydrofuran,followed by ethyl ester hydrolysis by the procedure set forth in Example106.

Example 132 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method in Example 33 with thetitle compound of Example 105 and (S)-3-hydroxytetrahydrofuran, followedby ethyl ester hydrolysis by the procedure set forth in Example 106.

Example 133 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by the method in Example 33 with thetitle compound of Example 105 and

followed by ethyl ester hydrolysis by the procedure set forth in Example106.

Example 134 Compound of Formula II, wherein A=-(C═O)—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 105 in 4 ml of a 4M solution of HCl in dioxane andstirring the reaction mixture for 1 hour. The reaction residue isconcentrated in vacuo. To this residue, 4 ml of THF and 0.045 mmol ofTEA is added, the mixture is cooled to 0° C., to which is added 0.045mmol of the cyclopental acid chloride. The resulting reaction mixture isstirred for 2 hours at 0° C. The reaction mixture is then extracted withEtOAc, washed with 1M sodium bicarbonate, water and brine, dried overMgSO₄ and concentrated to dryness in vacuo. The crude compound ispurified by silica column and the ethyl ester is subsequently hydrolyzedby the procedure set forth in Example 106.

Example 135 Compound of Formula II, wherein A=-(C═O)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 105 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. The resulting reaction residue is concentrated invacuo, dissolved in 4 ml THF, and cooled to 0° C. To the 0° C. solutionis added 0.045 mmol of cyclopentyl isocyanate and the resulting reactionmixture is stirred at RT for 4 hours. The solution is then extractedwith EtOAc, washed with 1% HCl, water and brine, dried over MgSO₄, andconcentrated in vacuo to dryness. The crude compound is purified bysilica column and the ethyl ester is subsequently hydrolyzed by theprocedure set forth in Example 106.

Example 136 Compound of Formula II, wherein A=-(C═S)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 105 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. The resulting reaction residue is concentrated invacuo, dissolved in 4 ml THF, and cooled to 0° C. To the 0° C. solutionis added 0.045 mmol of cyclopentyl isothiocyanate and the resultingreaction mixture is stirred at RT for 4 hours. The solution is thenextracted with EtOAc, washed with 1% HCl, water and brine, dried overMgSO₄, and concentrated in vacuo to dryness. The crude compound ispurified by silica column and the ethyl ester is subsequently hydrolyzedby the procedure set forth in Example 106.

Example 137 Compound of Formula II, wherein A=-S(O)₂—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R ³═R ⁴═H

The title compound is prepared by dissolving 0.041 mmol of the titlecompound from Example 105 in 4 ml of a 4M solution of HCl in dioxane andstirring for 1 hour. To the resulting concentrated reaction residue,which has been dissolved in 4 ml THF, is added 0.045 mmol of TEA, andcooled to 0° C. To the 0° C. solution is added 0.045 mmol of cyclopentylsolfonyl chloride and the resulting reaction mixture is stirred at 0° C.for 2 hours. The solution is then extracted with EtOAc, washed with 1Msodium bicarbonate, water and brine, dried over MgSO₄, and concentratedin vacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 106.

Example 138 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-O-phenethyl, L=absent, W is

X=phenyl, Y=phenyl, i=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 128 and phenethyl alcohol 138a in 0.5 ml DCM, isadd1.2 eq PyBrOP 4 eq. DIEA, and catalytic amount of DMAP at 0° C. Theresulting reaction mixture is stirred for 1 hour at 0° C. and thenwarmed to RT over a period of 4-12 hours. The reaction mixture ispurified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound isolated phenethyl ester 138b.

Other esters can be made using the same procedures.

Example 139 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NH-phenethyl, L=absent, W is

X=phenyl, Y=phenyl j=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 128 and phenethylamine 139a (0.05 ml) in 0.5 ml DMF,EDC (1.2 eq.) and DIEA (4 eq.) at 0° C. The resulting reaction mixtureis stirred at 1 hour. Subsequently, the reaction is warmed to RT over aperiod of 4-12 hours. The reaction mixture is purified by silica gelflash chromatography using different ratios of hexanes:EtOAc as elutionphase (9:1→5:1→3:1→1:1) to afford title compound phenethyl amide 139b.Other amides can be made using the same procedures.

Example 140 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NHS(O)₂-phenethyl, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and R3=R4=H

The title compound is prepared by adding to a solution of the titlecompound of Example 128 and α-toluenesulfonamide 140a (10 mg) in 0.5 mlDCM, is added 1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAPat 0° C. The resulting reaction mixture is stirred for 1 hour and thenallowed to warm to RT over a period of 4-12 hours. The reaction mixtureis purified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound sulfonamide 140b.

Other sulfonamides can be made using the same procedure.

Example 141 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—OH, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and and R³═R⁴═H

The title compound is prepared by adding to a solution of the titlecompound of Example 128 in 0.5 ml THF, is addedα-hydroxy-α-methyl-propionitrile (0.1 ml) and catalytic amount TFA at 0°C. The resulting reaction mixture is warmed from 0° C. to RT over aperiod of 4-12 h followed by hydrolysis with concentrated hydrochloricacid in dioxane. The reaction is then extracted with EtOAc, and washedwith water and brine to yield α-hydroxy compound 141a in its crude form.The crude compound 46b undergoes a Dess-Martin oxidation in THF (0.5ml), providing the a-carbonyl compound 46b in crude form. The crude 141bis purified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound isolated keto acid 141c.

Example 142 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—O-phenethyl, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 141 and phenethanol according to the procedure set forth inExample 138.

Example 143 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH-phenethyl, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 141 and phenethyl amine according to the procedure set forth inExample 139.

Example 144 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH—S(O)₂-benzyl, L=absent, W is

X=phenyl, Y=phenyl, j=3, m=s=1, and and R³═R⁴═H

The title compound is prepared with the title compound keto acid ofExample 141 and α-toluenesulfonamide according to the procedure setforth in Example 140.

Example 145 Compound of Formula II, wherein A=tBOC, G=OH, L=—(C═O)CH₂—,W is

X=phenyl, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 88C and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 146 Compound of Formula II, wherein A=tBOC, G=OH,L=-CH(CH₃)CH₂—, W is

X=phenyl, Y=phenyl, j=1, m=s=1, R³=methyl, and R⁴═H

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 89G and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 147 Compound of Formula II, wherein A=tBOC, G=OH, L=-O—, W is

X=phenyl, Y=phenyl, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 90D and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 148 Compound of Formula II, wherein A=tBOC, G=OH, L=—S—, W is

X=phenyl, Y=phenyl, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 91E and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 149 Compound of Formula II, wherein A=tBOC, G=OH, L=-S(O)—, W is

X=phenyl, Y=phenyl, j=2, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 92B and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 150 Compound of Formula II, wherein A=tBOC, G=OH, L=-S(O)₂—, Wis

X=phenyl, Y=phenyl, j=2, m=s=1, R³=methyl, and R⁴═H

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 93B and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 151 Compound of Formula II, wherein A=tBOC, G=OH, L=-SCH₂CH₂—, Wis

X=phenyl, Y=phenyl, j=0, m=s=1, and R³═R⁴═CH₃

L-Penicillamine 151a is dissolved in DMF/DMSO (5:1), subsequently,4-bromopentene and CsOH.H₂O are added to the mixture and stirring iscontinued for an additional 12 hours. The DMF is subsequently removed invacuo, the remaining mixture is diluted with 0.5 N HCl (at 0° C.) toadjust the pH to ˜4-5 and then extracted with 2 portions of EtOAc. Theorganic phase is washed with brine (2×), dried over MgSO₄ and evaporatedto dryness to afford the crude carboxylic acid 151a.

151B. Synthesis of Modified Cyclic Peptide Precursor Mesylate

The modified cyclic peptide precursor mesylate is prepared using thesynthetic route detailed in Example 1 using the modified amino acid 151ain place of Boc-L-2-amino-8-nonenoic acid 1a followed by conversion tothe corresponding mesylate via the method described in Example 2.

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 151B and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 152 Compound of Formula II, wherein A=tBOC, G=OH, L=CF₂CH₂, W is

X=phenyl, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 95C and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 153 Compound of Formula II, wherein A=tBOC, G=OH, L=-CHFCH₂—, Wis

X=phenyl, Y=phenyl, j=1, m=s=1, and R³═R⁴═H

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in Example 96C and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 154 Compound of Formula III, wherein A=tBOC, G=OH, L=absent, Wis

X=phenyl, Y=phenyl, j=3, m=s=1, and R³═R⁴═H

154A. The saturated cyclic peptide precursor mesylate is prepared bycatalytic reduction of the mesylate cyclic peptide precursor 2 with Pd/Cin MeOH in the presence of H₂.

The title compound is prepared with the saturated cyclic peptideprecursor mesylate formed in 154A and 4,5-diphenyltriazole by thereplacement method elucidated in Example 105 followed by hydrolysis ofthe ethyl ester via the method set forth in Example 106.

Example 155 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

j=3, m=s=1, and R³═R⁴═H

155A. Substituted benzotriazole formation

The bromo-substituted benzotriazole 155b of the present Example isprepared by combining 2.15 g (10 mmol) of 5-bromo-3,4-dimethylbenzene-1,2-diamine, 1.15 ml (20 mmol) of glacial acetic acid,and 10 ml of water and heating the resulting mixture to obtain a clearsolution. The clear solution is then cooled to 5° C., a cold solution of0.83 g (12 mmol) of sodium nitrite in 5 ml of water is added, and thereaction mixture is heated to 70˜80° C. for 2 hours. The reactionmixture is then extracted with EtOAc, washed by brine and water, driedover Na₂SO₄, and concentrated in vacuo. The crude product is purified bysilica column.

155B. Replacement

The ethyl ester 155c is prepared by the replacement method described inExample 105 with the title compound of Example 2 and bromo-substitutedbenzotriazole 155b.

The title compound is ultimately prepared with ethyl ester 155c by thehydrolysis procedure set forth in Example 106.

Example 156 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

j=3, m=s=1,and R³═R⁴═H

Compound 156a of the present Example is prepared via a Suzuki couplingreaction with 155c and 3-thienyl boronic acid as described in Example26C.

156B. Hydrolysis

The title compound is prepared with ethyl ester 156a by the hydrolysisprocedure set forth in Example 106.

Example 157 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, W is

j=3, m=s=1,and R³═R⁴═H

157a. Bicyclic Compound Formation

The bicyclic compound of the present invention is prepared with 2,3-diaminopyridine by the procedure set forth in Example 157A.

The title compound is prepared with the bicyclic compound prepared in157a and the title compound of Example 2 by the replacement methoddescribed in Example 105, followed by hydrolysis of the ethyl ester viathe procedure set forth in Example 106.

Example 158 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X═Y=bromo, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

To a mixture of macrocyclic compound 1 (185 mg, 0.38 mmol),4,5-dibromo-2H-pyridazin-3-one (95 mg, 0.38 mmol) and triphenylphosphine(197 mg, 0.75 mmol) in THF (5 mL) is added DIAD (148 μL, 0.75 mmol)dropwise at 0° C. After stirring at 0° C. for 15 min., the solution iswarmed to room temperature and is further stirred for 16 hours. Themixture is then concentrated in vacuo and the residue is purified bycolumn chromatography eluting with 40% ethyl acetate-hexane to give 235mg (86%) of the title compound.

¹H-NMR (500 MHz, CDCl₃) δ (ppm): 7.8 (s, 1H), 7.1 (brs, 1H), 5.5 (m,2H), 5.2 (m, 2H), 5.0 (m, 1H), 4.4 (brt, 1 H), 4.0-4.2 (m, 4H), 2.9 (m,1H), 2.6 (m, 1H), 1.8-2.3 (m, 5H), 1.4 (s, 9H), 1.2 (t, 3H).[M+H]=730.6.

Example 159 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, and R³ ═R⁴ ═hydrogen

A mixture of the title compound of Example 162 (40 mg, 0.055 mmol),3-thiophene boronic acid (35mg, 0.28 mmol), cesium carbonate (71 mg,0.22 mmol), potassium fluoride monohydrate (41 mg, 0.44 mmol) is placedin a round bottom flask and is flushed twice with nitrogen. To thismixture is added DME and the resulting solution is flushed again withnitrogen before palladium tetrakis(triphenylphopshine) (7 mg, 10 mol %)is added. After flushing two more times with nitrogen, the mixture isheated to reflux for 20 hours. The mixture is then cooled and thendiluted with water and extracted three times with EtOAc. The combinedEtOAc layers are washed once with brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue is purified by column chromatographyeluting with 20-40% EtOAc-hexane to give the title compound as a clearfilm (24 mg, 60%).

¹H-NMR (500 MHz, CDCl₃) δ (ppm): 7.9 (s, 1H), 7.6 (s, 1H), 7.3 (s, 1H),7.3 (m, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6.8 (d, 1H), 5.7 (m, 1H), 5.5 (m,1H), 5.4 (brd, 1H), 5.2 (t, 1H), 5.0 (m, 1H), 4.6 (brt, 1H), 4.0-4.2 (m,4H), 2.9 (m, 1H), 2.6 (m, 1H), 2.0-2.3 (m, 5H), 1.4 (s, 9H), 1.2 (t,3H). [M+Na]⁺=758.63.

Example 160 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

To a solution of the title compound in Example 2 (24 mg, 0.033 mmol) inTHF/MeOH/H₂O (2/1/0.5 mL) is added lithium hydroxide (14 mg, 0.33 mmol).After stirring for 16 hours at room temperature, the mixture isacidified to pH 4 with citric acid and extracted three times with EtOAc.The combined organic extracts are washed once with brine, dried (MgSO₄),filtered and concentrated in vacuo. The residue is purified by columnchromatography eluting with 5-10% methanol-chloroform to give the titlecompound (13 mg, 56%).

[M+H]⁺=708.3.

Example 161 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=phenyl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling withphenylboronic acid and the title compound of Example 158 according tothe procedure set forth in Example 159, followed by hydrolysis of theethyl ester via the method described in Example 160.

[M+H]⁺=696.40

Example 162 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=4-(N,N-dimethylamino)phenyl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling with4-(N,N-dimethylamino)phenyl boronic acid and the title compound ofExample 158 according to the procedure set forth in Example 159,followed by hydrolysis of the ethyl ester via the method described inExample 160.

[M+H]=782.30

Example 163 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=4-(trifluoromethoxy)phenyl, Z=hydrogen, j=3, m=s=1, and R³═R⁴hydrogen

The title compound is prepared by a double Suzuki coupling with4-(trifluoromethoxy)phenyl boronic acid and the title compound ofExample 158 according to the procedure set forth in Example 159,followed by hydrolysis of the ethyl ester via the method described inExample 160.

[M+H]⁺=864.09

Example 164 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=4-(methanesulfonyl)phenyl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling with4-(methanesulfonyl)phenyl boronic acid and the title compound of Example158 according to the procedure set forth in Example 159, followed byhydrolysis of the ethyl ester via the method described in Example 160.

Example 165 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=4-(cyano)phenyl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling using4-cyanophenyl boronic acid and the title compound of Example 158according to the procedure set forth in Example 159, followed byhydrolysis of the ethyl ester via the method described in Example 160.

[M+H]⁺=746.14

Example 166 Compound of Formula II, wherein A=tBOC, G=OH. L=absent,X═Y=pyrid-3-yl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling using3-pyridyl boronic acid and the title compound of Example 158 accordingto the procedure set forth in Example 159, followed by hydrolysis of theethyl ester via the method described in Example 160.

[M+H]⁺=698.3.

Example 167 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=4-(morpholin-4-yl-methanonyl)phenyl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by a double Suzuki coupling using4-carboxyphenyl boronic acid and the title compound of Example 158according to the procedure set forth in Example 159, followed by amideformation with morpholine, under standard amide bond formationconditions, e.g. PyBrOP, DIEA, and DMAP in DMF. The ethyl ester of theresulting compound is then hydrolyzed via the hydrolysis procedure ofExample 160.

Example 168 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=bromo, Y=methoxy. Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared from the title compound in Example 158via hydrolysis of the ethyl ester according to the procedure describedin Example 160, however addition of methoxy to the 5 position isobserved in addition to hydrolysis of the ethyl ester.

[M+H]⁺=652.2, 654.2.

Example 169 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, Xand Y taken together=phenyl, Z=4-methoxypheny, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared according to the Mitsunobu conditions setforth in Scheme 20 with commercially available4-(4-methoxy-phenyl)-2H-phthalazin-1-one, and subsequent hydrolysis ofthe ethyl ester via the procedure of Example 160.

[M+H]⁺=700.1.

Example 170 Compound of Formula II, wherein A =tBOC, G=OH, L=absent, Xand Y taken together=phenyl, Z=4-chlorophenyl, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared according to the Mitsunobu conditions setforth in Scheme 20 with commercially available4-(4-chloro-phenyl)-2H-phthalazin-1-one, and subsequent hydrolysis ofthe ethyl ester via the procedure of Example 160.

[M+H]⁺=704.2.

Example 171 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=4-fluorophenyl, Y=hydrogen, Z=phenyl, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared according to the Mitsunobu conditions setforth in Scheme 20 with commercially available4-(4-fluoro-phenyl)-6-phenyl-2H-pyridazin-3-one, and subsequenthydrolysis of the ethyl ester via the procedure of Example 160.

[M+H]⁺=704.2.

Example 172 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=hydrogen, Y=1-piperidyl, Z=phenyl, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared according to the Mitsunobu conditions setforth in Scheme 20 with commercially available6-phenyl-5-piperidin-1-yl-2H-pyridazin-3-one, and subsequent hydrolysisof the ethyl ester via the procedure of Example 160.

[M+H]⁺=702.3.

Example 173 Compound of Formula II, wherein A=tBOC, G 32 OEt, L 32absent, X=hydrogen, Y=bromo, Z=phenyl, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared according to the Mitsunobu conditions setforth in Scheme 20 with commercially available5-Bromo-6-phenyl-2H-pyridazin-3-one.

[M+H]⁺=726.3, 728.3.

Example 174 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=hydrogen, Y=thiophen-3-yl, Z=phenyl, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound of Example 173and thiophen-3-yl boronic acid according to the Suzuki couplingconditions described in Example 159, followed by the hydrolysis of theethyl ester via the method described in Example 160.

[M+H]⁺730.3

Example 175 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X=bromo, Y=1-pyrrolidyl, Z=hydrogen, J=3, m 32 s=1, and R³═R⁴=hydrogen

A mixture of the title compound in Example 158 (45 mg, 0.062 mmol),pyrrolidine (21 mL, 0.25 mmol), and potassium carbonate (34 mg, 0.25mmol) in 2 mL of acetonitrile is heated to reflux for 3 hours. Aftercooling to room temperature, the mixture is filtered through a sinterglass funnel and the filtrate is concentrated in vacuo. The residue isre-dissolved in ethyl acetate and then washed once with saturated sodiumcarbonate, once with brine, dried (MgSO4), filtered, and concentratedunder vacuum to give a yellow residue which is chromatographed oversilica gel eluting with 3% methanol-chloroform to give 37 mg (83%) ofthe title compound.

[M+H]⁺=719.2, 721.2

Example 176 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=thiophen-3-yl, Y=1-pyrrolidyl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared with the title compound in Example 175and thiephen-3-yl boronic acid using the Suzuki conditions described inExample 159, followed by hydrolysis of the ethyl ester according to themethod set forth in Example 160.

[M+H]⁺=694.3.

Example 177 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X=bromo, Y=azido, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

A mixture of the title compound in Example 158 (45 mg, 0.062 mmol),sodium azide (16 mg, 0.25 mmol), and potassium carbonate (34 mg, 0.25mmol) in 2 mL of acetonitrile is heated to reflux for 3 hours. Aftercooling to room temperature, the mixture is filtered through a sinterglass funnel and the filtrate is concentrated in vacuo. The residue isre-dissolved in ethyl acetate and then washed once with saturated sodiumcarbonate, once with brine, dried (MgSO₄), filtered, and concentratedunder vacuum to give a yellow residue which is chromatographed oversilica gel eluting with 3% methanol-chloroform to give 37 mg (83%) ofthe title compound.

Example 178 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X=thiophen-3-yl, Y=azido, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound in Example 177and thiophen-3-yl boronic acid using the Suzuki conditions described inExample 159.

Example 179 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=thiophen-3-yl, Y=azido, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by hydrolysis of the ethyl ester of thetitle compound of Example 178 via the hydrolysis procedure of Example160. Example 180. Compound of Formula II, wherein A=tBOC, G 32 OH,L=absent, X=thiophen-3-yl, Y=tetrazol-2-yl, Z=hydrogen, J=3 m=s=1, andR³═R⁴=hydrogen

To a solution of the title compound of Example 178 (2.63 mmol) intoluene (8 ml) is added KCN (10.53 mmol) and Et₃N*HCl (10.53 mmol). Themixture is heated at 115° C., for 18 hrs, diluted with DCM, washed with5% citric acid (aq), dried over anhydrous Na₂SO₄, and concentrated invacuo to afford the ethyl ester of the title compound in crude form.Hydrolysis of the ethyl ester via the method described in Example 160yields the title compound.

Example 181

Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=mercapto-2-pryrimidine, Z=hydrogen, j=3, m=s =1, and R³═R⁴=hydrogen

A mixture of the title compound in Example 158 (45 mg, 0.062 mmol),pyrimidine-2-thiol (0.25 mmol), and potassium carbonate (34 mg, 0.25mmol) in 2 mL of acetonitrile is heated to reflux for 3 hours. Aftercooling to room temperature, the mixture is filtered through a sinterglass funnel and the filtrate is concentrated in vacuo. The residue isre-dissolved in ethyl acetate and then washed once with saturated sodiumcarbonate, once with brine, dried (MgSO4), filtered, and concentratedunder vacuum to give a yellow residue which is chromatographed oversilica gel eluting with 3% methanol-chloroform to afford 181b in a 19%yield. The ethyl ester of compound 181b is then hydrolyzed via themethod described in Example 160 to give the title compound.

[M+H]⁺=764.3.

Example 182 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=bromo, Y=mercapto-2-pryrimidine, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by hydrolysis of the ethyl ester ofcompound 181a, formed in Example 181, via the method set forth inExample 160.

[M+H]⁺=732.2, 734.2.

Example 183 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=thiophen-3-yl, Y=mercapto-2-pryrimidine, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared with compound 181 a from Example 181 andthiophen-3-yl boronic acid according to the Suzuki coupling conditionsset forth in Example 159, followed by hydrolysis of the ethyl ester viathe method described in Example 160.

Example 184 Compound of Formula II, wherein A=tBOC, G=OEt, L=absent,X═Y=thiazol-2-yl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

To a degassed solution of the title compound of Example 158 (1 mmol) andthiazol-2-yl stannane (2 mmol) is added Pd(PPh₃)₄ (10 mol %). Themixture is degassed with nitrogen 2 more times and is heated to 100° C.for 3 hour. The cooled mixture is concentrated under vacuum and theresidue is purified by column chromatography eluting with 30%EtOAc/Hexane followed by the hydrolysis of the ethyl ester via themethod of Example 160 to give the title compound.

[M+H]⁺=710.3.

Example 185 Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X═Y=imidazol-1-yl, Z=hydrogen, J=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by adding to a dry mixture of the titlecompound from Example 158 (0.068 mmol), imidazole (2 eq.), Cs₂CO₃ (3eq.), Xantphos (30 mol %), and Pd(OAc)₂ under nitrogen dioxane. Thereaction mixture is then degassed and stirred at 75° C. for 18 hours.Upon completion of the reaction, monitored via TLC, the reaction mixtureis diluted with DCM, filtered, and concentrated in vacuo. The reactionmixture is then purified via silica column chromatography with 5%MeOH/CHCl₃ to afford the ethyl ester of the title compound. The ethylester is then hydrolyzed by the conditions set forth in Example 160 toafford the title compound.

Example 186. Compound of Formula II, wherein A=tBOC, G=OH, L=absent,X=2-(cyclopropylamino)-thiazol-4-yl, Y=4-methoxphenyl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen Formation of4-(2-Cyclopropylamino-thiazol-4-yl)-5-(4-methoxy-phenyl)-2H-Pyridazin-3-one(186h)

186A. A mixture of commercially available 4,5-dichloropyridazin3(2H)-one(18 mmol), benzyl bromide (19 mmol), potassium carbonate (45 mmol),tetrabutylammonium bromide (1 mmol) and acetonitrile (45 mL) is stirredand heated under reflux for 1 h. After cooling, the solvent isevaporated under reduced pressure. The residue is purified by filtrationon a small silica gel column eluting with 10% EtOAc/Hexane to givecompound 186a as a white powder (81%). [M+H]⁺=256.3.

186B. To a magnetically stirred solution of 186a (4.5 mmol) in drydioxane (20 mL) is added 1.0 mL of 21 wt % solution of sodium methoxideat room temperature. After 1 hour, the mixture is poured intowater/ethyl acetate and the organic layer is dried over MgSO₄ andconcentrated to an oil. The oil residue is purified by columnchromatography eluting with 10% EtOAc/Hex to give 85% of 186b.[M+H]⁺=251.7.

Alternate substitution of pyridazinone 186b can be achieved via thisstep using MeOH rather than dioxane as a solvent, wherein the methoxyoccupies the 5 position on the pyridazinone ring and the chloro residesat the 4 position.

186C. Pyridazinone 186b (1 mmol) is dissolved in DME. To this mixture isadded Pd(PPh₃)₄ (10 mol %) and the mixture is stirred at roomtemperature for 10 min before 4 methoxybenzeneboronic acid (2 mmol) andaqueous 1 mL of Na₂CO₃ (10 wt %) are added. Subsequently, the reactionmixture is heated to reflux for 18 hours. The cooled reaction mixture isdiluted with water and extracted 3 times with ethyl acetate. Thecombined organic layers are dried (MgSO₄), filtered and concentratedunder vacuum. The residue is purified by column chromatography on silicagel eluting with 15% EtOAc/Hexane to give compound 186c. [M+H]⁺=323.3.

186D. To a solution of 186c (3 mmol) in DME is added 2N KOH and theresulting mixture is heated to reflux for 1 hour. The cooled mixture isdiluted with water and acidified with solid citric acid to pH 5 andextracted 3 times with CH₂Cl₂. The organic layers are washed once withbrine, dried (MgSO₄), filtered and concentrated under vacuum to givecompound 186d. [M+H]⁺=309.3.

186E. To a cooled solution of compound 186d (2 mmol), triethylamine (0.4mL) in dichloromethane (10 mL) (ice-acetone bath) is addedtrifluoromethanesulfonic anhydride (0.4 mL) dropwise. The resultingsolution is stirred for 30 min at −5° C. The reaction mixture is thenpoured into dilute HCl (0.5 M) and extracted with CH₂Cl₂. The combinedorganic layers are washed with a 1% NaHCO₃, brine and dried (MgSO₄),filtered and concentrated under vacuum to give a brown oil. Compound186e is used immediately without further purification. [M+H]⁺=441.4.

186F. Commercially available 2,4-dibromothiazole (2 mmol) is dissolvedin cyclopropylamine (3 mL) and the reaction mixture is heated to 50° C.for 8 hour. The cooled mixture is then poured into water and extracted 2times with ether. After drying the combined organic fractions (MgSO₄),evaporation of solvents, and purification by flash column chromatography(silica gel, 15% EtOAc/Hexane) furnished2-cyclopropylamine-4-bromothiazole which is further converted to thecorresponding stannane 186f. A solution of2-cyclopropylamine-4-bromothiazole in degassed DME is treated withhexamethylditin and Pd(PPh₃)₄ and heated at 80° C. for 18 hour. Thecooled mixture is concentrated under vacuum and the residue is purifiedby column chromatography eluting with 20% EtOAc/Hexane/2% Et₃N to giveStannane 186f. [M+H]⁺=304.1.

186G. To a degassed solution of compound 186e (1 mmol) and stannane 186f(2 mmol) is added Pd(PPh₃)₄ (10 mol %). The mixture is degassed twoadditional times with nitrogen and subsequently heated to 100° C. for 3hour. The cooled mixture is concentrated under vacuum and the residue ispurified by column chromatography eluting with 30% EtOAc/Hexane to givecompound 186g. [M+H]⁺=431.6.

186H. A solution of compound 186g and 10% Pd/C (wet) in MeOH issubjected to a hydrogen balloon for 2 hours. The mixture is filteredthrough a pad of celite and the filtrate is concentrated under vacuum togive compound 186h. [M+H]⁺=341.4.

The title compound is prepared from pyridazinone 186h and the cyclicpeptide precursor 1 of Example 1 via the Mitsunobu conditions set forthin Example 158, followed by the hydrolysis of the ethyl ester via thehydrolysis conditions described in Example 159.

Example 187 Compound of Formula II, wherein A=tBOC, G=OH, L=absent, Xand Y taken together=6-methoxy-isoquinolin-(3,4)-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

187A. Pyridazinone 186b (2 mmol) is dissolved in DME. To this mixture isadded Pd(PPh₃)₄ and the mixture is stirred at room temperature for 10min before 2-formyl-4- methoxybenzeneboronic acid and aqueous Na₂CO₃ (10wt %) are added. Subsequently, the reaction mixture is heated to refluxfor 18 hours. The cooled reaction mixture is diluted with water andextracted 3 times with ethyl acetate. The combined organic layers aredried (MgSO₄), filtered and concentrated under vacuum. The residue ispurified by column chromatography on silica gel eluting with 20%EtOAc/Hexane to give compound 187a. [M+H]⁺=351.4.

187B. A mixture of pyridazinone 187a (1 mmol), MeOH (20 mL) and NH₄OH(10 mL, 28-30 wt %) is heated at 60° C. for 30 min. After cooling, theprecipitate, compound 187b, is filtered and rinsed with MeOH (15 mL).[M+H]⁺=317.4.

187C. A mixture of pyridazinoisoquinolinone 187b (0.5 mmol), AlCl₃ andtoluene is stirred and heated at 70° C. for 1 hour. After cooling, wateris added and the mixture is filtered and rinsed with water. The residueis purified by column chromatography on silica gel eluting with 50%EtOAc/Hex to give compound 187c. [M+H]⁺=227.3.

The title compound is prepared from pyridazinoisoquinolinone 187c andthe cyclic peptide precursor 1 of Example 1 via the Mitsunobu conditionsset forth in Example 162, followed by the hydrolysis of the ethyl estervia the hydrolysis conditions described in Example 159.

Example 188 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

188a—Amine Deprotection.

0.041 mmol of the title compound of Example 159 is dissolved in 4 ml ofa 4M solution of HCl in dioxane and stirred for 1 hour. The reactionresidue 188a is concentrated in vacuo.

188b—Chloroformate Reagent

The chloroformate reagent 188b is prepared by dissolving 0.045 mmol ofcyclopentanol in THF (3 ml) and adding 0.09 mmol of phosgene in toluene(20%). The resulting reaction mixture is stirred at room temperature for2 hours and the solvent is removed in vacuo. To the residue is added DCMand subsequently concentrated to dryness twice in vacuo yieldingchloroformate reagent 188b.

188c—Carbamate Formation

The title carbamate is prepared by dissolving residue 188a in 1 ml ofTHF, adding 0.045 mmol of TEA, and cooling the resulting reactionmixture to 0° C. To this 0° C. reaction mixture is added chloroformatereagent 188b in 3 ml of THF. The resulting reaction mixture is reactedfor 2 hours at 0° C., extracted with EtOAc, washed by 1M sodiumbicarbonate, water and brine, dried over MgSO₄, and concentrated invacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 160.

Example 189 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclobutyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by the method described in Example 188with the title compound of Example 159 and cyclobutanol.

Example 190 Compound of Formula II, wherein A=-(C═O)—O—R¹, whereinR¹=cyclohexyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by the method described in Example 188with the title compound of Example 159 and cyclohexanol.

Example 191 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by the method described in Example 188with the title compound of Example 159 and (R)-3-hydroxytetrahydrofuran.

Example 192 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by the method described in Example 188with the title compound of Example 159 and (S)-3-hydroxytetrahydrofuran.

Example 193 Compound of Formula II, wherein A=-(C═O)—O—R¹, wherein R¹═

G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, andR³═R⁴=hydrogen

The title compound is prepared by the method described in Example 188with the title compound of Example 159 and

Example 194 Compound of Formula II, wherein A=-(C═O)—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound from Example 159in 4 ml of a 4M solution of HCl in dioxane and stirring the reactionmixture for 1 hour. The reaction residue is concentrated in vacuo. Tothis residue, 4 ml of THF and 0.045 mmol of TEA is added, the mixture iscooled to 0° C., to which is added 0.045 mmol of the cyclopentyl acidchloride. The resulting reaction mixture is stirred for 2 hours at 0° C.The reaction mixture is then extracted with EtOAc, washed with 1M sodiumbicarbonate, water and brine, dried over MgSO₄ and concentrated todryness in vacuo. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 160.

Example 195 Compound of Formula II, wherein A=-(C═O)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R^(3 l ═R) ⁴=hydrogen

The title compound is prepared with the title compound from Example 159in 4 ml of a 4M solution of HCl in dioxane and stirring for 1 hour. Theresulting reaction residue is concentrated in vacuo, dissolved in 4 mlTHF, and cooled to 0° C. To the 0° C. solution is added 0.045 mmol ofcyclopentyl isocyanate and the resulting reaction mixture is stirred atRT for 4 hours. The solution is then extracted with EtOAc, washed with1% HCl, water and brine, dried over MgSO₄, and concentrated in vacuo todryness. The crude compound is purified by silica column and the ethylester is subsequently hydrolyzed by the procedure set forth in Example160.

Example 196 Compound of Formula II, wherein A=-(C═S)—NH—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound from Example 159in 4 ml of a 4M solution of HCl in dioxane and stirring for 1 hour. Theresulting reaction residue is concentrated in vacuo, dissolved in 4 mlTHF, and cooled to 0° C. To the 0° C. solution is added 0.045 mmol ofcyclopentyl isothiocyanate and the resulting reaction mixture is stirredat RT for 4 hours. The solution is then extracted with EtOAc, washedwith 1% HCl, water and brine, dried over MgSO₄, and concentrated invacuo to dryness. The crude compound is purified by silica column andthe ethyl ester is subsequently hydrolyzed by the procedure set forth inExample 160.

Example 197 Compound of Formula II, wherein A=-S(O)₂—R¹, whereinR¹=cyclopentyl, G=OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen, j=3,m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound from Example 159in 4 ml of a 4M solution of HCl in dioxane and stirring for 1 hour. Tothe resulting concentrated reaction residue, which has been dissolved in4 ml THF, is added 0.045 mmol of TEA, and cooled to 0° C. To the 0° C.solution is added 0.045 mmol of cyclopentyl sulfonyl chloride and theresulting reaction mixture is stirred at 0° C. for 2 hours. The solutionis then extracted with EtOAc, washed with 1M sodium bicarbonate, waterand brine, dried over MgSO₄, and concentrated in vacuo to dryness. Thecrude compound is purified by silica column and the ethyl ester issubsequently hydrolyzed by the procedure set forth in Example 160.

Example 198 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-O-phenethyl, L=absent, X═Y=thiophen-3-yl, Z=hydrogen,JU=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by adding to a solution of the titlecompound of Example 194 and phenethyl alcohol 198a in 0.5 ml DCM, isadded 1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAP at 0° C.The resulting reaction mixture is stirred for 1 hour at 0° C. and thenwarmed to RT over a period of 4-12 hours. The reaction mixture ispurified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound isolated phenethyl ester 198b.

Other esters can be made using the same procedures.

Example 199 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NH-phenethyl, L=absent, X═Y=thiophen-3-yl,Z=hydrogen, j=3,. m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by adding to a solution of the titlecompound of Example 194 and phenethylamine 199a (0.05 ml) in 0.5 ml DMF,EDC (1.2 eq.) and DIEA (4 eq.) at 0° C. The resulting reaction mixtureis stirred at 1 hour. Subsequently, the reaction is warmed to RT over aperiod of 4-12 hours. The reaction mixture is purified by silica gelflash chromatography using different ratios of hexanes:EtOAc as elutionphase (9:1→5:1→3:1→1:1) to afford title compound phenethyl amide 199b.

Other amides can be made via the same procedure.

Example 200 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-NHS(O)₂-phenethyl, L=absent X═Y=thiophen-3-yl,Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared by adding to a solution of the titlecompound of Example 194 and α-toluenesulfonamide 200a (10 mg) in 0.5 mlDCM, is added 1.2 eq. PyBrOP, 4 eq. DIEA, and catalytic amount of DMAPat 0° C. The resulting reaction mixture is stirred for 1 hour and thenallowed to warm to RT over a period of 4-12 hours. The reaction mixtureis purified by silica gel flash chromatography using different ratios ofhexanes:EtOAc as elution phase (9:1→5:1→3:1→1:1) to afford the titlecompound sulfonamide 200b.

Other sulfonamides can be made via the same procedure.

Example 201 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—OH, L=absent, X═Y=thiophen-3-yl, Z=hydrogen,j=3, m=s=1, and and R³═R⁴=hydrogen

The title compound is prepared by adding to a solution of the titlecompound of Example 194 in 0.5 ml DMF, EDC (1.2 eq.) and DIEA (4 eq.) at0° C. The resulting reaction mixture is stirred at 1 hour. Subsequently,the reaction is warmed to RT over a period of 4-12 hours. The reactionmixture is purified by silica gel flash chromatography to affordhydroxyamide. The hydroyamide is then treated with DIBAL-H at −78° C. inTHF for 2 hours. The reaction mixture is then diluted with 8 ml EtOAc,washed with water and brine, dried over Na₂SO₄, and concentrated invacuo to yield aldehyde 201a. To a solution of aldehyde 39a in 0.5 mlTHF, is added α-hydroxy-α-methyl-propionitrile (0.1 ml) and catalyticamount TFA at 0° C. The resulting reaction mixture is warmed from 0° C.to RT over a period of 4-12 hours followed by hydrolysis withconcentrated hydrochloric acid in dioxane. The reaction is thenextracted with EtOAc, and washed with water and brine to yield a-hydroxycompound 201b in its crude form. The crude compound 201b undergoes aDess-Martin oxidation in THF (0.5 ml), providing the α-carbonyl compound201c in crude form. The crude 201c is purified by silica gel flashchromatography using different ratios of hexanes:EtOAc as elution phase(9:1→5:1→3:1→1:1) to afford the title compound isolated keto acid 201c.

Example 202 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—O—phenethyl, L=absent. X═Y=thiophen-3-yl,Z=hydrogen, j=3, m=s=1, and and R³═R⁴=hydrogen

The title compound is prepared with the title compound keto acid ofExample 201 and phenethanol according to the procedure set forth Example198.

Example 203 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH-phenethyl, L=absent, X═Y=thiophen-3-yl,Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound keto acid ofExample 201 and phenethyl amine according to the procedure set forth inExample 199.

Example 204 Compound of Formula II, wherein A=-(C═O)—O—R¹,R¹=cyclopentyl, G=-(C═O)—NH—S(O)₂-benzyl, L=absent, X═Y=thiophen-3-yl,Z=hydrogen, J=3, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the title compound keto acid ofExample 201 and α-toluenesulfonamide according to the procedure setforth in Example 200.

Example 205 Compound of Formula II, wherein A=tBOC, G=OH, L=-(C═O)CH₂,X═Y=thiophen-3-yl, Z=hydrogen, j=1, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 88C and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 206 Compound of Formula II, wherein A=tBOC, G=OH, L=-CH(CH₃)CH₂,X═Y=thiophen-3-yl, Z=hydrogen, j=1, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 89G and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 207 Compound of Formula II, wherein A=tBOC, G=OH, L=-O—,X═Y=thiophen-3-yl, Z=hydrogen, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 90D and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 208 Compound of Formula II, wherein A=tBOC, G=OH, L=-S—.X═Y=thiophen-3-yl, Z=hydrogen, j=0, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 91E and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 209 Compound of Formula II, wherein A=tBOC, G=OH, L=-S(O)—,X═Y=thiophen-3-yl, Z=hydrogen, j=2, m=s=1, R³=methyl, and R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 92B and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 210 Compound of Formula II, wherein A=tBOC, G=OH,L=-S(O)₂X═Y=thiophen-3-yl, Z=hydrogen, j=2, m=s=1, R³=methyl, andR⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 93B and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 211 Compound of Formula II, wherein A=tBOC, G=OH, L=-SCH₂CH₂,X═Y=thiophen-3-yl, Z=hydrogen, j=0, m=s=1, and R³═R⁴═CH₃

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 94B and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 212 Compound of Formula II, wherein A=tBOC, G=OH, L=CF₂CH₂,X═Y=thiophen-3-yl, Z=hydrogen, j=1, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 95C and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 213 Compound of Formula II, wherein A=tBOC, G=OH, L=-CHFCH₂—,X═Y=thiophen-3-yl, Z=hydrogen, j=1, m=s=1, and R³═R⁴=hydrogen

The title compound is prepared with the modified cyclic peptideprecursor mesylate formed in 96C and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

Example 214 Compound of Formula III, wherein A=tBOC, G=OH, L=absent,X═Y=thiophen-3-yl, Z=hydrogen, j=3, m=s=1, and R³═R⁴=hydrogen

214A. The saturated cyclic peptide precursor mesylate is prepared bycatalytic reduction of the mesylate cyclic peptide precursor of Example2 with Pd/C in MeOH in the presence of H₂.

The title compound is prepared with the saturated cyclic peptideprecursor mesylate formed in 214A and4,5-di(thiophen-3-yl)-2H-pyridazin-3-one by the Mitsunobu conditionselucidated in Example 158 followed by hydrolysis of the ethyl ester viathe method set forth in Example 160.

The compounds of the present invention exhibit potent inhibitoryproperties against the HCV NS3 protease. The following exampleselucidate exemplary assays in which the compounds of the presentinvention are tested for anti-HCV effects.

Example 215 NS3/NS4a Protease Enzyme Assay

HCV protease activity and inhibition is assayed using an internallyquenched fluorogenic substrate. A DABCYL and an EDANS group are attachedto opposite ends of a short peptide. Quenching of the EDANS fluorescenceby the DABCYL group is relieved upon proteolytic cleavage. Fluorescencewas measured with a Molecular Devices Fluoromax (or equivalent) using anexcitation wavelength of 355 nm and an emission wavelength of 485 nm.

The assay is run in Corning white half-area 96-well plates (VWR29444-312 [Corning 3693]) with full-length NS3 HCV protease 1b tetheredwith NS4A cofactor (final enzyme concentration 1 to 15 nM). The assaybuffer is complemented with 10 μM NS4A cofactor Pep 4A (Anaspec 25336 orin-house, MW 1424.8). RET S1(Ac-Asp-Glu-Asp(EDANS)-Glu-Glu-Abu-[COO]Ala-Ser-Lys-(DABCYL)-NH₂,.AnaSpec22991, MW 1548.6) is used as the fluorogenic peptide substrate. Theassay buffer contained 50 mM Hepes at pH 7.5, 30 mM NaCl and 10 mM BME.The enzyme reaction is followed over a 30 minutes time course at roomtemperature in the absence and presence of inhibitors.

The peptide inhibitors HCV Inh 1 (Anaspec 25345, MW 796.8)Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, [31 20° C.] and HCV Inh 2 (Anaspec 25346,MW 913.1) Ac-Asp-Glu-Dif-Cha-Cys-OH, were used as reference compounds.

IC50 values were calculated using XLFit in ActivityBase (IDBS) usingequation 205: y=A+((B−A)/(1+((C/x){circumflex over ( )}D))).

Example 216 Cell-Based Replicon Assay

Quantification of HCV Replicon RNA in Cell Lines (HCV Cell Based Assay)

Cell lines, including Huh-11-7 or Huh 9-13, harboring HCV replicons(Lohmann, et al Science 285:110-113,1999) are seeded at 5×10³ cells/wellin 96 well plates and fed media containing DMEM (high glucose), 10%fetal calf serum, penicillin-streptomycin and non-essential amino acids.Cells are incubated in a 5% CO₂ incubator at 37° C. At the end of theincubation period, total RNA is extracted and purified from cells usingQiagen Rneasy 96 Kit (Catalog No. 74182). To amplify the HCV RNA so thatsufficient material can be detected by an HCV specific probe (below),primers specific for HCV (below) mediate both the reverse transcriptionof the HCV RNA and the amplification of the cDNA by polymerase chainreaction (PCR) using the TaqMan One-Step RT-PCR Master Mix Kit (AppliedBiosystems catalog no. 4309169). The nucleotide sequences of the RT-PCRprimers, which are located in the NS5B region of the HCV genome, are thefollowing: HCV Forward primer “RBNS5bfor” 5′GCTGCGGCCTGTCGAGCT: HCVReverse primer “RBNS5Brev”: 5′CAAGGTCGTCTCCGCATAC

Detection of the RT-PCR product was accomplished using the AppliedBiosystems (ABI) Prism 7700 Sequence Detection System (SDS) that detectsthe fluorescence that is emitted when the probe, which is labeled with afluorescence reporter dye and a quencher dye, is processed during thePCR reaction. The increase in the amount of fluorescence is measuredduring each cycle of PCR and reflects the increasing amount of RT-PCRproduct. Specifically, quantification is based on the threshold cycle,where the amplification plot crosses a defined fluorescence threshold.Comparison of the threshold cycles of the sample with a known standardprovides a highly sensitive measure of relative template concentrationin different samples (ABI User Bulletin #2 Dec. 11, 1997). The data isanalyzed using the ABI SDS program version 1.7. The relative templateconcentration can be converted to RNA copy numbers by employing astandard curve of HCV RNA standards with known copy number (ABI UserBulletin #2 Dec. 11, 1997).

The RT-PCR product was detected using the following labeled probe:5′ FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA

-   -   FAM=Fluorescence reporter dye.    -   TAMRA:=Quencher dye.

The RT reaction is performed at 48°C. for 30 minutes followed by PCR.Thermal cycler parameters used for the PCR reaction on the ABI Prism7700 Sequence Detection System were: one cycle at 95° C., 10 minutesfollowed by 35 cycles each of which included one incubation at 95° C.for 15 seconds and a second incubation for 60° C. for 1 minute.

To normalize the data to an internal control molecule within thecellular RNA, RT-PCR is performed on the cellular messenger RNAglyceraldehydes-3-phosphate dehydrogenase (GAPDH). The GAPDH copy numberis very stable in the cell lines used. GAPDH RT-PCR is performed on thesame exact RNA sample from which the HCV copy number is determined. TheGAPDH primers and probes, as well as the standards with which todetermine copy number, are contained in the ABI Pre-Developed TaqManAssay Kit (catalog no. 4310884E). The ratio of HCV/GAPDH RNA is used tocalculate the activity of compounds evaluated for inhibition of HCV RNAreplication.

Activity of Compounds as Inhibitors of HCV Replication (Cell BasedAssay) in Replicon Containing Huh-7 Cell Lines

The effect of a specific anti-viral compound on HCV replicon RNA levelsin Huh-11-7 or 9-13 cells was determined by comparing the amount of HCVRNA normalized to GAPDH (e.g. the ratio of HCV/GAPDH) in the cellsexposed to compound versus cells exposed to the 0% inhibition and the100% inhibition controls. Specifically, cells were seeded at 5×10³cells/well in a 96 well plate and were incubated either with: 1) mediacontaining 1% DMSO (0% inhibition control), 2) 100 international units,IU/ml Interferon-alpha 2b in media/1% DMSO or 3) media/1% DMSOcontaining a fixed concentration of compound. 96 well plates asdescribed above were then incubated at 37° C. for 3 days (primaryscreening assay) or 4 days (IC50 determination). Percent inhibition wasdefined as:

-   -   % Inhibition=[100-((S—C2)/C1-C2))]×100    -   where    -   S=the ratio of HCV RNA copy number/GAPDH RNA copy number in the        sample;    -   C1=the ratio of HCV RNA copy number/GAPDH RNA copy number in the        0% inhibition control (media/1% DMSO); and    -   C2=the ratio of HCV RNA copy number/GAPDH RNA copy number in the        100% inhibition control (100 IU/ml Interferon-alpha 2b).

The dose-response curve of the inhibitor was generated by addingcompound in serial, three-fold dilutions over three logs to wellsstarting with the highest concentration of a specific compound at 10 uMand ending with the lowest concentration of 0.01 uM. Further dilutionseries (1 uM to 0.001 uM for example) was performed if the IC50 valuewas not in the linear range of the curve. IC50 was determined based onthe IDBS Activity Base program using Microsoft Excel “XL Fit” in whichA=100% inhibition value (100 IU/ml Interferon-alpha 2b), B=0% inhibitioncontrol value (media/1% DMSO) and C=midpoint of the curve as defined asC═(B-A/2)+A . A, B and C values are expressed as the ratio of HCVRNA/GAPDH RNA as determined for each sample in each well of a 96 wellplate as described above. For each plate the average of 4 wells wereused to define the 100% and 0% inhibition values.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

1. A compound having the Formula I:

wherein: A is selected from the group consisting of H, —(C═O)—R²,—(C═O)—O—R¹, —C═O)—NH—R², —C(═S)—NH—R², —S(O)₂—R², —(C═NR—^(1 )−R) ¹,and —(C═NR¹)—NH—R¹; G is selected from the group consisting of —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R¹, —(C═O)—O—R¹, and—(C═O)—NH—R¹; L is selected from the group consisting of absent, —S—,—SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,—OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and—CR_(x)═CR_(x)— where R_(x)═H or halogen; j is 0, 1, 2, 3, or 4; m is 0,1, or 2; s is 0, 1 or 2; R¹ is selected form the group consisting of H,C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; R² is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, alkylamino,dialkylamino, arylamino, diarylamino, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, andsubstituted heterocycloalkyl; R³ and R⁴ are each independently selectedfrom the group consisting of hydrogen, OH, CH₃, CN, SH, halogen, NO₂,NH₂, amide, methoxy, trifluoromethoxy, and trifluoromethyl; E isselected from —CH═CH— or —CH₂—CH₂—; and W is a substituted orunsubstituted heterocyclic ring system.
 2. A compound according to claim1 wherein W is substituted with one or more substituents, each of saidsubstituents being independently selected from any of (a), (b), (c), (d)and (e): (a) alkenyl; alkoxy; alkoxyalkyl; alkyl; alkylamino; alkylaryl;alkylsulfonyl; alkynyl; amide; amido optionally mono-substituted withC₁-C₆ alkyl; aryl; arylalkanoylalkyl; arylalkyl; arylaminoalkyl;aryloxyalkyl; arylsulfonyl; cycloalkoxy; cycloalkyl; dialkylamino;dialkylaminoalkyl; diarylaminoalkyl; haloalkyl; heteroaryl;heteroarylalkyl; heterocyclo; heterocycloalkyl; heterocycloalkylalkyl;thioalkyl; monoalkylaminoalkyl; sulfonyl; (lower alkyl)sulfonyl;haloalkyl; carboxyl; amide; (lower alkyl)amide; heterocyclo optionallysubstituted with C₁-C₆ alkyl; perhaloalkyl; sulfonyl; thioalkyl; urea,C(═O)—R¹¹; OC(═O)R¹¹; C(═O)O—R¹¹; C(═O)N(R¹¹)₂; C(═S)N(R¹¹)₂; SO₂R¹¹;NHS(O₂)R¹¹; N(R¹²)₂; N(R¹²)C(═O)R¹¹; wherein each of the foregoing canbe optionally be substituted with up to three groups selected fromhalogen, OH, alkoxy, perhaloalkyl; (b) C₇-C₁₄ aralkyl; C₂-C₇cycloalkyl;C₆-C₁₀ aryl; heterocyclo; (lower alkyl)-heterocyclo; wherein eacharalkyl, cycloalkyl, aryl, heterocyclo or (lower alkyl)-heterocyclo maybe optionally substituted with R⁶, where R⁶ is halogen, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkoxy, NO₂, N(R⁷)₂,NH—C(O)—R⁷ or NH—C(O)—NHR⁷; where R⁷ is H, C₁-C₆ alkyl or C₃-C₆cycloalkyl; or R⁶ is NH—C(O)—OR⁸ where R⁸ is C₁-C₆ alkyl or C₃-C₆cycloalkyl; (c) N(R⁵)₂, NH—C(O)—R⁵, or NH—C(O)—NH—R⁵ where R⁵ isindependently H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, C₆ or C₁₀ aryl, C₇-C₁₄aralkyl, heterocyclo or (lower alkyl)-heterocyclo; (d) NH—C(O)—OR⁸ whereR⁸ is C₁-C₆ alkyl or C₃-C₆ cycloalkyl; (e) formyl; halogen;, hydroxy;NO₂; OH; SH; halo; CN; wherein each R¹¹ is independently H, OH, alkyl,alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl,heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl,heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl,alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl,arylaminoalkyl, diarylaminoalkyl, wherein any of the foregoing can beoptionally be substituted with up to three groups selected from halogen,OH, alkoxy and perhaloalkyl; and each R¹² is independently H, formyl,alkyl, alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl,alkylaryl, heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl,heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkylaryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, ordiarylaminoalkyl, wherein any of the foregoing can be optionally besubstituted with up to three groups selected from halogen, OH, alkoxyand perhaloalkyl.
 3. The compound of claim 1 wherein W is selected fromthe group consisting of: (a) an aliphatic heteromonocyclic,heterobicyclic or heterotricyclic ring system having from five tosixteen ring atoms and up to four ring hetero atoms selected from O, Nand S, wherein said ring system is optionally substituted with up tothree ring substituents selected from the group consisting of OH, CN,halogen, formyl, R¹⁰ and R¹¹; and (b) an aromatic heteromonocyclic,heterobicyclic or heterotricyclic ring system having from five tosixteen ring atoms and up to four ring hetero atoms selected from O, Nand S, wherein said ring system is optionally substituted with up tothree ring substituents selected from the group consisting of OH, CN,halogen, formyl, and R¹⁰; wherein: each R¹⁰ is independently alkyl,alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl,heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heretoaryl,heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl,alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl,arylaminoalkyl, diarylaminoalkyl, heteroaryl or urea, wherein any of theforegoing can be optionally be substituted with up to three groupsselected from halogen, OH, alkoxy and perhaloalkyl; C(═O)—R¹¹,OC(═O)R¹¹, C(═O)O—R¹¹, C(═O)N(R¹¹)₂, C(═S)N(R¹¹)₂, SO₂R¹¹, NHS(O₂)R¹¹,N(R¹²)₂, and N(R¹²)C(═O)R¹¹; each R¹¹ is independently H, OH, alkyl,alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl,heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl, heteroaryl,heteroarylalkyl, arylalkanoylalkyl, heterocycloalkylalkyl aryloxyalkyl,alkylamino, dialkylamino, monoalkylaminoalkyl, dialkylaminoalkyl,arylaminoalkyl, diarylaminoalkyl, wherein any of the foregoing can beoptionally be substituted with up to three groups selected from halogen,OH, alkoxy and perhaloalkyl; each R¹² is independently H, formyl, alkyl,alkenyl, alkynyl, perhaloalkyl, alkoxy, aryl, arylalkyl, alkylaryl,heterocyclo, heterocycloalkyl, alkylsulfonyl, arylsulfonyl,heteroarylalkyl, heteroaryl, arylalkanoylalkyl, heterocycloalkylalkylaryloxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, ordiarylaminoalkyl, wherein any of the foregoing can be optionally besubstituted with up to three groups selected from halogen, OH, alkoxyand perhaloalkyl.
 4. The compound of claim 3 wherein W is an aliphaticheteromonocyclic, heterobicyclic or heterotricyclic ring system havingfrom five to sixteen ring atoms and up to four ring hetero atomsselected from O, N and S, wherein said ring system is optionallysubstituted with up to three ring substituents selected from the groupconsisting of OH, CN, halogen, formyl, R₁₀ and R₁₁.
 5. The compound ofclaim 3 wherein W is an aliphatic heteromonocyclic ring system havingfrom five to seven ring atoms and up to four ring hetero atoms selectedfrom O, N and S, wherein said ring system is optionally substituted withup to three ring substituents selected from the group consisting of OH,CN, halogen, formyl, R¹⁰ and R¹¹.
 6. The compound of claim 5 herein saidoptionally substituted aliphatic heteromonocyclic ring system has fivering atoms and 1 or 2 ring hetero atoms selected from O, N and S.
 7. Thecompound of claim 6 wherein said optionally substituted aliphaticheteromonocyclic ring system is selected from the group consisting ofpyrrolidines, pyrazolidines, pyrrolines, tetrahydrothiophenes,dihydrothiophenes, tetrahydrofurans, dihydrofurans, imidazolines,tetrahydroimidazoles, dihydropyrazoles, tetrahydropyrazoles, andoxazolines.
 8. The compound of claim 5 wherein said optionallysubstituted aliphatic heteromonocyclic ring system has six ring atomsand 1 or 2 ring hetero atoms selected from O, N and S.
 9. The compoundof claim 8 wherein said optionally substituted aliphaticheteromonocyclic ring system is selected from the group consisting ofpyridines, piperidines, dihydropyridines, tetrahydropyridines,dihydropyrans, tetrahydropyrans, dioxanes, piperazines,dihydropyrimidines, tetrahydropyrimidines, perhydro pyrimidine,morpholine, thioxane, and thiomorpholine.
 10. The compound of claim 5wherein said optionally substituted aliphatic heteromonocyclic ringsystem has seven ring atoms and 1 or 2 ring hetero atoms selected fromO, N and S.
 11. The compound of claim 8 wherein said optionallysubstituted aliphatic heteromonocyclic ring system is selected from thegroup consisting of hexamethyleneimine, and hexamethylenesulfide. 12.The compound of claim 3 wherein W is an aliphatic heterobicyclic ringsystem having from five to sixteen ring atoms and up to four ring heteroatoms selected from O, N and S, wherein said ring system is optionallysubstituted with up to three ring substituents selected from the groupconsisting of OH, CN, halogen, formyl and R₁₀.
 13. The compound of claim12 wherein said optionally substituted aliphatic heterobicyclic ringsystem has eight to twelve ring atoms and 1 to 4 ring hetero atomsselected from O, N and S.
 14. The compound of claim 13 wherein saidoptionally substituted aliphatic heterobicyclic ring system eight totwelve ring atoms and 1 or 2 ring hetero atoms selected from O and N.15. The compound of claim 3 wherein W is an aromatic heteromonocyclic,heterobicyclic or heterotricyclic ring system having from five tosixteen ring atoms and up to four ring hetero atoms selected from O, Nand S, wherein said ring system is optionally substituted with up tothree ring substituents selected from the group consisting of OH, CN,halogen, formyl and R₁₀.
 16. The compound of claim 3 wherein W is anaromatic heteromonocyclic ring system having from five to seven ringatoms and up to four ring hetero atoms selected from O, N and S, whereinsaid ring system is optionally substituted with up to three ringsubstituents selected from the group consisting of OH, CN, halogen,formyl and R₁₀.
 17. The compound of claim 15 wherein said optionallysubstituted aromatic heteromonocyclic ring system has five ring atomsand 1 or 2 ring hetero atoms selected from O, N and S.
 18. The compoundof claim 17 wherein said optionally substituted aromaticheteromonocyclic ring system is selected from the group consisting ofpyrroles, pyrazoles, porphyrins, furans, thiophenes, pyrazoles,imidazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles,and isothiazoles.
 19. The compound of claim 16 wherein said optionallysubstituted aromatic heteromonocyclic ring system has six ring atoms and1, 2 or 3 ring hetero atoms selected from O, N and S.
 20. The compoundof claim 19 wherein said optionally substituted aromaticheteromonocyclic ring system is selected from the group consisting ofpyridines, pyrimidines, pyrazines, pyrans, and triazines.
 21. Thecompound of claim 16 wherein said optionally substituted aromaticheteromonocyclic ring system has five ring atoms and 3 or 4 ring heteroatoms selected from O, N and S.
 22. The compound of claim 21 whereinsaid optionally substituted aromatic heteromonocyclic ring system istriazolyl or tetrazolyl.
 23. The compound of claim 3 wherein W is anaromatic heterobicyclic ring system having from eight to twelve ringatoms and up to four ring hetero atoms selected from O, N and S, whereinsaid ring system is optionally substituted with up to three ringsubstituents selected from the group consisting of OH, CN, halogen,formyl and R₁₀.
 24. The compound of claim 23 wherein said optionallysubstituted aromatic heterobicyclic ring system is selected from thegroup consisting of adenines, azabenzimidazoles, azaindoles,benzimidazoles, benzo isothiazoles, benzofurans, benzoisoxazoles,benzooxazoles, benzothiadiazoles, benzothiazoles, benzothienes,benzothiophenes, benzoxazoles, carbazoles, cinnolines, guanines,imidazopyridines, indazoles, indoles, isoindoles, isoquinolines,phthalazines, purines, pyrrolo pyridines, quinazolines, quinolines,quinoxalines, thianaphthenes, and xanthines.
 25. The compound of claim 3wherein W is an aromatic heterotricyclic ring system having from ten tosixteen ring atoms and up to four ring hetero atoms selected from O, Nand S, wherein said ring system is optionally substituted with up tothree ring substituents selected from the group consisting of OH, CN,halogen, formyl, R₁₀ and R₁₁,
 26. The compound of claim 25 wherein saidoptionally substituted aromatic heterotricyclic ring system is selectedfrom the group consisting of carbazoles, bibenzofurans, psoralens,dibenzothiophenes, phenazines, thianthrenes, phenanthrolines,phenanthridines.
 27. A compound of Formula II

Wherein: A is selected from the group consisting of H, —(C═O)—R²,—(C═O)—O—R¹, —C(═O)—NH—R¹, —C(═S)—NH—R² , —S(O)₂—R², —(C═NR¹)—R¹, and—(C═NR¹)—NH—R¹; G is selected from the group consisting of —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R¹, and—(C═O)—NH—R²; L is selected from the group consisting of absent, —S—,—SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,—OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and—CR_(x)═CR_(x)— where R_(x)═H or halogen; W is selected from the groupconsisting of

Q is selected from the group consisting of absent, —CH₂—, —O—, —NH—,—N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from the groupconsisting of absent, —CH₂—, and —NH—; Y is selected from the groupconsisting of H, C₁-C₆ alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, andsubstituted heterocycloalkyl; j=0, 1, 2, 3, or 4; m=0, 1, or 2; s=0,1or2; R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, andsubstituted heterocycloalkyl; R² is selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; and R³ and R⁴ areeach independently selected from the group consisting of hydrogen andmethyl.
 28. A compound according to claim 27, wherein: A is —(C═O)—O—R¹;G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen. 29.A compound according to claim 27, wherein: A is —(C═O)—O-tert-butyl; Gis hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.
 30. Acompound according to claim 27, wherein: A is —(C═O)—O—R¹, G ishydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.
 31. Acompound according to claim 27, wherein: A is —(C═O)—O-tert-butyl; G ishydroxyl; L is absent; W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 32. A compound according toclaim 27 which is selected from the group consisting of: j = 3; m = s =1; and A G L W Q Y R³, R⁴ tBOC OH absent

absent phenyl R³ = R⁴ = H; tBOC OH absent

absent 2-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 3-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 4-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 5-bromo-2-thienyl R³ = R⁴ = H; tBOC OH absent

absent 2-bromo-4-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 2-biphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-biphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-biphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-(3-thienyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-(p-trifluoromethoxyphenyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-(p-cyanophenyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 4-(3-thienyl)phenyl R³ = R⁴ = H; tBOC OH absent

=absent 4-(p-trifluoromethoxyphenyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 4-(p-cyanophenyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 5-phenyl-2-thienyl R³ = R⁴ = H; tBOC OH absent

absent 5-phenyl-3-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-hydroxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-hydroxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-bromo-4-hydroxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 2-methyl-4-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 3-methyl-4-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent n-propyl R³ = R⁴ = H; tBOC OH absent

absent n-butyl R³ = R⁴ = H; tBOC OH absent

absent 4-ethoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-propoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-butoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-methoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3,4-dimethoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-methoxy-1-naphthyl R³ = R⁴ = H; tBOC OH absent

absent 4-phenoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent benzyl R³ = R⁴ = H; tBOC OH absent

absent p-phenylbenzyl R³ = R⁴ = H; tBOC OH absent

absent 3-chlorophenyl R³ = R⁴ = H; tBOC OH absent

absent 3-fluorophenyl R³ = R⁴ = H; tBOC OH absent

absent 3-methoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-phenoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-benzyloxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-trifluoromethylphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 4-fluorophenyl R³ = R⁴ = H; tBOC OH absent

absent 4-methoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-ethoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 4-trifluoromethylphenyl R³ = R⁴ = H; tBOC OH absent

absent 3,5-di(trifluoromethyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 4-(N,N-dimethylamino)-3,5-di(trifluoromethyl)phenyl R^(3 = R) ⁴ =H; tBOC OH absent

absent 2,4-dichlorophenyl R³ = R⁴ = H; tBOC OH absent

absent 3,5-dichlorophenyl R³ = R⁴ = H; tBOC OH absent

absent 3,4-dichlorophenyl R³ = R⁴ = H; tBOC OH absent

absent 2-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 2-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 3-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 4-pyridyl R³ = R⁴ = H; tBOC OH absent

absent 4-methoxy-3-bromophenyl R³ = R⁴ = H; tBOC OH absent

absent 4-(methylcyclopropane)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-(methylcyclopropane)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-methoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-ethoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-bromo-4-ethoxyphenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-(2-hydroxyethoxy)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-bromo-4-(2-hydroxyethoxy)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-(O-allyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-bromo-4-(O-allyl)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-(O—CH₂SCH₃)phenyl R³ = R⁴ = H; tBOC OH absent

absent 3-chloro-4-(O—CH₂SCH₃)phenyl R³ = R⁴ = H; tBOC OH absent

wherein Q′ = —CH₂—

R³ = R⁴ = H; and tBOC OH absent

wherein Q′ = —CH₂—

R³ = R⁴ = H.


33. A compound according to claim 27 which is selected from the groupconsisting of: j = 3; m = s = 1; and A G L W Q Y R³ , R⁴ —(C═O)—O—R¹wherein R¹ = cyclopentyl OH absent

absent phenyl R³ = R⁴ = H; —(C═O)—O—R¹ wherein R¹ = cyclobutyl OH absent

absent phenyl R³ = R⁴ = H; wherein A = —(C═O)—O—R¹ wherein R¹ =cyclohexyl OH absent

absent phenyl R³ = R⁴ = H;

OH absent

absent phenyl R³ = R⁴ = H;

OH absent

absent phenyl R³ = R⁴ = H; and

OH absent

absent phenyl R3 = R4 = H


34. A compound according to claim 27 which is selected from the groupconsisting of: m = s = 1; and A G L W Q Y j m, s R³, R⁴ tBOC OH—(C═O)CH₂—

absent phenyl 1 m = s = 1 R³ = R⁴ = H; tBOC OH —CH(CH₃)CH₂—

absent phenyl 1 m = s = 1 R³ = methyl, R⁴ = H tBOC OH —O—

absent phenyl 0 m = s = 1 R³ = methyl, R⁴ = H tBOC OH —S—

absent phenyl 0 m = s = 1 R³ = methyl, R⁴ = H tBOC OH —S(O)—

absent phenyl 0 m = s = 1 R³ = methyl, R⁴ = H; tBOC OH —S(O)₂—

absent phenyl 0 m = s = 1 R³ = methyl, R⁴ = H tBOC OH —SCH₂CH₂—

absent phenyl 0 m = s = 1 R³ = R⁴ = CH₃; tBOC OH —CF₂CH₂—

absent phenyl 1 m = s = 1 R³ = R⁴ = H; and tBOC OH —CFHCH₂—

absent phenyl 1 m = s = 1 R³ = R⁴ = H


35. A compound according to claim 27 which is selected from the groupconsisting of: A G L W j m, s R³, R⁴ —(C═O)—O—R¹R¹ = cyclopentyl−O-phenethyl absent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl —NH-phenethylabsent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl—NHS(O)₂-phenethyl absent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl —(C═O)—OHabsent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl—(C═O)—O-phenethyl absent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl—(C═O)—NH-phenethyl absent

j = 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹R¹ = cyclopentyl—(C═O)—NH—S(O)₂-benzyl absent

j = 3 m = s = 1 R³ = R⁴ = H.


36. A compound of Formula III:

wherein A is selected from the group consisting of H, —(C═O)—R²,—(C═O)—O—R¹, —C(═O)—NH—R², C(═S)—NH—R² , —S(O)₂—R², —(C═NR¹)—R¹, and—(C═NR¹)—NH—R¹; G is selected from the group consisting of —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R¹, and—(C═O)—NH—R²; L is selected from the group consisting of absent, —S—,—SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂‘, —S(O)—, —S(O)CH₂CH₂—, —O—,—OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and—CR_(x)═CR_(x)— where R_(x)═H or halogen; W is selected from the groupconsisting of

Q is selected from the group consisting of absent, —CH₂—, —O—, —NH—,—N(R¹)—, —S—, —S(O)₂—, and —(C═O)—; Q′ is selected from the groupconsisting of absent, —CH₂—, and —NH—; Y is selected from the groupconsisting of H. C₁-C₆ alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, andsubstituted heterocycloalkyl; j=0, 1, 2, 3, or 4; m=0, 1, or 2; s=0, 1or2; R¹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₁₂cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, andsubstituted heterocycloalkyl; R² is selected from the group consistingof H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl,alkylamino, dialkyl amino, arylamino, diarylamino, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; and R³ and R⁴ areeach independently selected from the group consisting of hydrogen andmethyl.
 37. A compound according to claim 36, wherein: A is —(C═O)—O—R¹;G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen. 38.A compound according to claim 36, wherein: A is —(C═O)—O—tert-butyl; Gis hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.
 39. Acompound according to claim 36, wherein: A is —(C═O)—O—R¹; G ishydroxyl; L is absent; W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 40. A compound according toclaim 36, wherein: A is —(C═O)—O-tert-butyl; G is hydroxyl; L is absent;W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 41. A compound of Formula II:

wherein A is selected from the group consisting of H, —(C═O)—R²,—(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R² , —S(O)₂—R², —(C═NR¹)—R¹, and—(C═NR¹)—NH—R¹; G is selected from the group consisting of —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R¹, and—(C═O)—NH—R²; L is selected from the group consisting of absent, —S—,—SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—, —S(O)CH₂CH₂—, —O—,—OCH₂—, —OCH₂CH₂-, —(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and—CR═CR)— where R_(x)═H or halogen; W is selected from the groupconsisting of and N Y

where X and Y are independently selected from the group consisting of H,halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,—CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino, —(C═O)-alkylamino,—(C═O)-dialkylamino, —(C═O)-arylamino, —(C═O)-diarylamino, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; in the alternative,X and Y taken together with the carbon atoms occupying the 4 and 5positions of the triazole ring, to which X and Y are attached, for acyclic moiety selected from the group consisting of aryl, substitutedaryl, heteroaryl, and substituted heteroaryl; j=0, 1, 2, 3, or4; m=0, 1,or 2; s=0, 1 or 2; R¹ is selected from the group consisting of H, C₁-C₆alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; R² is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; and R³ and R⁴ areeach independently selected from the group consisting of hydrogen andmethyl.
 42. A compound according to claim 41, wherein: A is —(C═O)—O—R¹;G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen. 43.A compound according to claim 41, wherein: A is —(C═O)—O-tert-butyl; Gis hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.
 44. Acompound according to claim 41, wherein: A is —(C═O)—O—R¹, G ishydroxyl; L is absent; W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 45. A compound according toclaim 41, wherein: A is —(C═O)—O-tert-butyl; G is hydroxyl; L is absent;W is

J=3; M=s=1; and R³ and R⁴ are hydrogen.
 46. A compound according toclaim 41 which is selected from the group consisting of: A G L W J m, sR³, R⁴ tBOC OH absent

X = Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

X = Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H. tBOC OH absent

X = n-propyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

X = m-methoxyphenyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H;tBOC OH absent

X = m-bromophenyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOCOH absent

X = 1-napthyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 2-thienyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 3-thienyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 4-pyrazolyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 3-pyridyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 2-pyridyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = 2-thiazolyl Y = p-methoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent

X = benzyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

X = n-butyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

X = n-propyl Y = n-propyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

X = 4-(N,N-dimethylamino)phenyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H;tBOC OH absent

X = (N,N-diethylamino)methyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H;tBOC OH absent

X = N,N-diethylaminocarbonyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H;tBOC OH absent

X = m-chlorophenyl Y = 4-ethoxyphenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOCOH absent

X = 2-phenylethenyl Y = phenyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OHabsent benzotriazole j =3 m = s =1 R³ = R⁴ = H; tBOC OH absent5,6-methylbenzotriazole j =3 m = s =1 R³ = R⁴ = H; and tBOC OH absent

X = N-ethylaminocarbonyl j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

j = 3 m = s = 1 R³ = R⁴ = H; tBOC OH absent

j = 3 m = s = 1 R³ = R⁴ = H; and tBOC OH absent

j = 3 m = s = 1 R³ = R⁴ = H.


47. A compound according to claim 41 which is selected from the groupconsisting of: A G L W J m, s R³, R⁴ —(C═O)—O—R¹wherein R¹ = cyclopentylOH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹wherein R¹ =cyclobutyl OH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹wherein R¹ =cyclohexyl OH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹wherein R¹ =

OH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H; —(C═O)—O—R¹wherein R¹ =

OH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H; and —(C═O)—O—R¹wherein R¹=

OH absent

X = phenyl Y = phenyl 3 m = s = 1 R³ = R⁴ = H.


48. A compound according to claim 41 which is selected from the groupconsisting of: A G L W J m, s R³ , R⁴ tBOC OH —(C═O)CH₂—

X = phenyl Y = phenyl 1 m = s = 1 R³ = R⁴ = H; tBOC OH —CH(CH₃)CH₂—

X = phenyl Y = phenyl 1 m = s = 1 R³ = methyl R⁴ = H; tBOC OH —O—

X = phenyl Y = phenyl 0 m = s = 1 R³ = methyl R⁴ = H; tBOC OH —S—

X = phenyl Y = phenyl 0 m = s = 1 R³ = methyl R⁴ = H; tBOC OH —S(O)—

X = phenyl Y = phenyl 2 m = s = 1 R³ = methyl R⁴ = H; tBOC OH —S(O)₂—

X = phenyl Y = phenyl 2 m = s = 1 R³ = methyl R⁴ = H; tBOC OH —SCH₂CH₂—

X = phenyl Y = phenyl 0 m = s = 1 R³ = R⁴ = CH_(3;) tBOC OH —CF₂CH₂—

X = phenyl Y = phenyl 1 m = s = 1 R³ = R⁴ = H; and tBOC OH —CFHCH₂—

X = phenyl Y = phenyl 1 m = s = 1 R³ = R⁴ = H.


49. A compound according to claim 41 which is selected from the groupconsisting of: A G L W J m, s R3, R4 —(C═O)—O—R¹R¹ = cyclopentyl—O-phenethyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R3 = R4 = H; —(C═O)—O—R¹R¹ =cyclopentyl —NH-phenethyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R3 = R4 = H; —(C═O)—O—R¹R¹ =cyclopentyl —NHS(O)₂-phenethyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R3 = R4 = H; —(C═O)—O—R¹R¹ =cyclopentyl —(C═O)—OH absent

X = phenyl Y = phenyl 3 m = s = 1 and and R³ = R⁴ = H; —(C═O)—O—R¹R¹ =cyclopentyl —(C═O)—O-phenethyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R³ = R⁴ = H; —(C═O)—O—R¹R¹ =cyclopentyl —(C═O)—NH-phenethyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R³ = R⁴ = H; and —(C═O)—O—R¹R¹ =cyclopentyl —(C═O)—NH—S(O)₂-benzyl absent

X = phenyl Y = phenyl 3 m = s = 1 and R³ = R⁴ = H.


50. A compound of Formula III:

wherein A is selected from the group consisting of H, —(C═O)—R²,—(C═O)—O—R¹, —C(═O)—NH—R², —C(═S)—NH—R² , —S(O)₂—R², —(C═NR¹)—R¹, and—(C═NR¹)—NH—R¹; G is selected from the group consisting of —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R¹, and—(C═O)—NH—R²; L is selected from the group consisting of absent, —S—,—SCH₂—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH2CH2-, —O—, —OCH₂—, —OCH₂CH₂—,—(C═O)—CH₂—, —CH(CH₃)CH₂—, —CFHCH₂—, —CF₂CH₂—, and —CR_(x)═CR_(x))—where R_(x)═H or halogen; from the group consisting of

where X and Y are independently selected from the group consisting of H,halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, —CH₂-alkylamino,—CH₂-dialkylamino, —CH₂-arylamino, —CH₂-diarylamino, —(C═O)-alkylamino,—(C═O)-dialkylamino, —(C═O)-arylamino, —(C═O)-diarylamino, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; in the alternative,X and Y taken together with the carbon atoms occupying the 4 and 5positions of the triazole ring, to which X and Y are attached, for acyclic moiety selected from the group consisting of aryl, substitutedaryl, heteroaryl, and substituted heteroaryl; j=0, 1, 2, 3, or 4; m=0,1, or 2; s=0, 1 or 2; R¹ is selected from the group consisting of H,C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; R² is selected fromthe group consisting of H, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, substitutedC₃-C₁₂ cycloalkyl, alkylamino, dialkyl amino, arylamino, diarylamino,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, and substituted heterocycloalkyl; and R³ and R⁴ areeach independently selected from the group consisting of hydrogen andmethyl.
 51. A compound according to claim 50, wherein: A is —(C═O)—O—R¹;G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen. 52.A compound according to claim 50, wherein: A is —(C═O)—O-tert-butyl; Gis hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ are hydrogen.
 53. Acompound according to claim 50, wherein: A is —(C═O)—O—R¹, G ishydroxyl; L is absent; W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 54. A compound according toclaim 50, wherein: A is —(C═O)—O-tert-butyl; G is hydroxyl; L is absent;W is

j=3; m=s=1; and R³ and R⁴ are hydrogen.
 55. A compound of Formula IV:

wherein A is hydrogen, —(C═O)—R¹ , —(C═O)—O—R¹, —C(═O)—NH—R²,—C(═S)—NH'R², —S(O)₂—R², —(C═NR¹)—R¹, or —(C═NR¹)—NH—R¹; G is —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R ¹, or—(C═O)—NH—R²; L is —S—, —SCH₂—, —SCH₂CH₂—, —S(O)²—, —S(O)²CH²CH²—,—S(O)—, —S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—,—CFHCH₂— —CF₂CH₂—, or —CR_(x)═CR_(x)— where R_(x)═H or halogen; X, Y,and Z are independently selected from the group consisting of hydrogen,N₃, halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, alkylamino, dialkylamino,C₁-C₆ alkynyl, substituted alkynyl, aryl, substituted aryl, —S-aryl,—S-substituted aryl, —O-aryl, —O-substituted aryl, NH-aryl,NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,—S-heteroaryl, —S-substituted heteroaryl, —O-heteroaryl, —O-substitutedheteroaryl, —NH-heteroaryl, —NH-substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; or, in the alternative, X and Y or Y and Z takentogether with the carbon atoms to which they are attached form an aryl,substituted aryl, heteroaryl, or substituted heteroaryl cyclic moiety;j=0, 1, 2, 3, or4; m=0, 1, or 2; s=0, 1 or 2; R¹ is hydrogen, C₁-C₆alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, or substituted heterocycloalkyl; R² is hydrogen, C₁-C₆alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, alkylamino,dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl; and R³ and R⁴ are each independentlyhydrogen or methyl.
 56. A compound according to claim 55, wherein: A is—(C═O)—O—R¹; G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ arehydrogen.
 57. A compound according to claim 55, wherein: A is—(C═O)—O-tert-butyl; G is hydroxyl; L is absent; j=3; m=s=1; and R³ andR⁴ are hydrogen.
 58. A compound according to claim 55 which is selectedfrom the group consisting of: A G L X, Y Z j m, s R³, R⁴ tBOC OEt absentX = Y = bromo hydrogen 3 m = s = 1 R³ = R⁴ = hydrogen; tBOC OEt absent X= Y = thiophen- hydrogen 3 m = s = 1 R³ = R⁴ = 3-yl hydrogen; tBOC OHabsent X = Y = thiophen- hydrogen 3 m = s = 1 R³ = R⁴ = 3-yl hydrogen;tBOC OH absent X = Y = phenyl hydrogen 3 m = s = 1 R³ = R⁴ = hydrogen;tBOC OH absent X = Y = 4-(N,N- hydrogen 3 m = s = 1 R³ = R⁴ =dimethylamino) hydrogen; phenyl tBOC OH absent X = Y = 4- hydrogen 3 m =s = 1 R³ = R⁴ = (trifluoromethoxy) hydrogen; phenyl tBOC OH absent X = Y= 4- hydrogen 3 m = s = 1 R³ = R⁴ = (methanesulfonyl) hydrogen; phenyltBOC OH absent X = Y = 4- hydrogen 3 m = s = 1 R³ = R⁴ = (cyano)phenylhydrogen; tBOC OH absent X = Y = 3-pyridyl hydrogen 3 m = s = 1 R³ = R⁴= hydrogen; tBOC OH absent X = Y = 4- hydrogen 3 m = s = 1 R³ = R⁴ =(morpholin-4-yl- hydrogen; methanonyl)phenyl tBOC OH absent X = Y =bromo hydrogen 3 m = s = 1 R³ = R⁴ = hydrogen; tBOC OH absent X and Ytaken 4- 3 m = s = 1 R³ = R⁴ = together = phenyl methoxyphenyl hydrogen;tBOC OH absent X and Y taken 4- 3 m = s = 1 R³ = R⁴ = together = phenylchlorophenyl hydrogen; tBOC OH absent X = 4-fluorophenyl phenyl 3 m = s= 1 R³ = R⁴ = Y = hydrogen hydrogen; tBOC OH absent Y = 1-piperidylphenyl 3 m = s = 1 R³ = R⁴ = hydrogen; tBOC OEt absent X = hydrogenphenyl 3 m = s = 1 R³ = R⁴ = Y = bromo hydrogen; tBOC OH absent X =hydrogen phenyl 3 m = s = 1 R³ = R⁴ = Y = thiophen-3-yl hydrogen; tBOCOEt absent X = bromo hydrogen 3 m = s = 1 R³ = R⁴ = Y = pyrrolid-1-ylhydrogen; tBOC OH absent X = thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴= Y = pyrrolid-1-yl hydrogen; tBOC OEt absent X = bromo hydrogen 3 m = s= 1 R³ = R⁴ = Y = azido hydrogen; tBOC OEt absent X = thiophen-3-ylhydrogen 3 m = s = 1 R³ = R⁴ = Y = azido hydrogen; tBOC OH absent X =thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = Y = azido hydrogen; tBOC OHabsent X = thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = Y =tetrazol-2-yl hydrogen; tBOC OH absent X = Y = hydrogen 3 m = s = 1 R³ =R⁴ = mercapto-2- hydrogen; pryrimidine tBOC OH absent X = bromo hydrogen3 m = s = 1 R³ = R⁴ = Y = hydrogen; mercapto-2- pryrimidine tBOC OHabsent X = thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = Y = hydrogen;mercapto-2- pryrimidine tBOC OH absent X = Y = thiazol-2- hydrogen 3 m =s = 1 R³ = R⁴ = yl hydrogen; tBOC OH absent X = Y = imidazol- hydrogen 3m = s = 1 R³ = R⁴ = l-yl hydrogen; tBOC OH absent X = 2- hydrogen 3 m =s = 1 R³ = R⁴ = (cyclopropylamino)- hydrogen; thiazol-4-yl Y = 4-methoxyphenyl tBOC OH absent X and Y taken hydrogen 3 m = s = 1 R³ = R⁴= together = 6- hydrogen methoxy- isoquinolinyl


59. A compound according to claim 55 which is selected from the groupconsisting of: A G L X, Y Z j m, s R³ , R⁴ —(C═O)—O—R¹ OH absent X =thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = wherein R¹ = Y =thiophen-3-yl hydrogen; cyclopentyl —(C═O)—O—R¹ OH absent X =thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = wherein R¹ = Y =thiophen-3-yl hydrogen; cyclobutyl —(C═O)—O—R¹ OH absent X =thiophen-3-yl hydrogen 3 m = s = 1 R³ = R⁴ = wherein R¹ = Y =thiophen-3-yl hydrogen; cyclohexyl —(C═O)—O—R¹wherein R¹ =

OH absent X = thiophen-3-yl Y = thiophen-3-yl hydrogen 3 m = s = 1 R³ =R⁴ =hydrogen; —(C═O)—O—R¹wherein R¹ =

OH absent X = thiophen-3-yl Y = thiophen-3-yl hydrogen 3 m = s = 1 R³ =R⁴ =hydrogen; and —(C═O)—O—R¹wherein R¹ =

OH absent X = thiophen-3-yl Y = thiophen-3-yl hydrogen 3 m = s = 1 R³ =R⁴ =hydrogen.


60. A compound according to claim 55 which is selected from the groupconsisting of: A G L X Y Z j m, s R³, R⁴ tBOC OH —(C═O)CH₂—thiophen-3-yl thiophen-3-yl hydro- 1 m = s = and R³ = R⁴ = gen 1hydrogen; tBOC OH —CH(CH₃)CH₂— thiophen-3-yl thiophen-3-yl hydro- 1 m =s = R³ = methyl gen 1 and R⁴ = hydrogen; tBOC OH —O— thiophen-3-ylthiophen-3-yl hydro- 0 m = s = R³ = methyl gen 1 and R⁴ = hydrogen; tBOCOH —S— thiophen-3-yl thiophen-3-yl hydro- 0 m = s = R³ = methyl gen 1and R⁴ = hydrogen; tBOC OH —S(O)— thiophen-3-yl thiophen-3-yl hydro- 2 m= s = R³ = methyl gen 1 and R⁴ = hydrogen; tBOC OH —S(O)₂— thiophen-3-ylthiophen-3-yl hydro- 2 m = s = R³ = methyl gen 1 and R⁴ = hydrogen; tBOCOH —SCH₂CH₂— thiophen-3-yl thiophen-3-yl hydro- 0 m = s = and R³ = R⁴ =gen 1 CH₃; tBOC OH —CF₂CH₂— thiophen-3-yl thiophen-3-yl hydro- 1 m = s =and R³ = R⁴ = gen 1 hydrogen; and tBOC OH —CFHCH₂— thiophen-3-ylthiophen-3-yl hydro- 1 m = s = and R³ = R⁴ = gen 1 hydrogen.


61. A compound according to claim 55 which is selected from the groupconsisting of: A G L X Y Z j m, s R³, R⁴ —(C═O)—O—R¹ —O-phenethyl absentthiophen- thiophen- hydrogen 3 m = s = R³ = R⁴ = R¹ = cyclopentyl 3-yl3-yl 1 hydrogen; —(C═O)—O—R¹ —NH- absent thiophen- thiophen- hydrogen 3m = s = R³ = R⁴ = R¹ = cyclopentyl phenethyl 3-yl 3-yl 1 hydrogen;—(C═O)—O—R¹ —NHS(O)₂- absent thiophen- thiophen- hydrogen 3 m = s = R³ =R⁴ = R¹ = cyclopentyl phenethyl 3-yl 3-yl 1 hydrogen; —(C═O)—O—R¹—(C═O)—OH absent thiophen- thiophen- hydrogen 3 m = s = R³ = R⁴ = R¹ =cyclopentyl 3-yl 3-yl 1 hydrogen; —(C═O)—O—R¹ —(C═O)—O- absent thiophen-thiophen- hydrogen 3 m = s = R³ = R⁴ = R¹ = cyclopentyl phenethyl 3-yl3-yl 1 hydrogen; —(C═O)—O—R¹ —(C═O)—NH- absent thiophen- thiophen-hydrogen 3 m = s = R³ = R⁴ = R¹ = cyclopentyl phenethyl 3-yl 3-yl 1hydrogen; and —(C═O)—O—R¹ —(C═O)—NH—S(O)₂- absent thiophen- thiophen-hydrogen 3 m = s = R³ = R⁴ = R¹ = cyclopentyl benzyl 3-yl 3-yl 1hydrogen.


62. A compound of Formula IV:

wherein A is hydrogen, —(C═O)—R¹, —(C═O)—O—R¹, —C(═O)—NH—R²,—C(═S)—NH—R², or —S(O)₂—R², —(C═NR¹)—R′, or —(C═NR¹)—NH—R¹; G is —OH,—O—(C₁-C₁₂ alkyl), —NHS(O)₂—R¹, —(C═O)—R², —(C═O)—O—R¹, or —(C═O)—NH—R²;L is absent, —S—, —SCH²—, —SCH₂CH₂—, —S(O)₂—, —S(O)₂CH₂CH₂—, —S(O)—,—S(O)CH₂CH₂—, —O—, —OCH₂—, —OCH₂CH₂—, —(C═O)—CH₂—, —CH(CH₃)CH₂—,—CFHCH₂—, —CF₂CH₂—, or —CR_(x)═CR— where R_(x)═H or halogen-; X, Y, andZ are independently selected from the group consisting of hydrogen, N₃,halogen, C₁-C₆ alkyl, C₃-C₁₂ cycloalkyl, alkylamino, dialkylamino, C₁-C₆alkynyl, substituted alkynyl, aryl, substituted aryl, —S-aryl,—S-substituted aryl, —O-aryl, —O-substituted aryl, NH-aryl,NH-substituted aryl, diarylamino, diheteroarylamino, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl,—S-heteroaryl, —S-substituted heteroaryl, —O-heteroaryl, —O-substitutedheteroaryl, —NH-heteroaryl, —NH-substituted heteroaryl, heteroarylalkyl,substituted heteroarylalkyl, heterocycloalkyl, and substitutedheterocycloalkyl; or, in the alternative, X and Y or Y and Z takentogether with the carbon atoms to which they are attached form an aryl,substituted aryl, heteroaryl, and substituted heteroaryl cyclic moiety;j=0, 1, 2, 3, or 4; m=0, 1, or 2; s=0, 1 or 2; R¹ is hydrogen, C₁-C₆alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-C₁₂ cycloalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycloalkyl, or substituted heterocycloalkyl; R² is hydrogen, C₁-C₆alkyl, C₃-C₁₂ cycloalkyl, substituted C₃-Cl₂ cycloalkyl, alkylamino,dialkyl amino, arylamino, diarylamino, aryl, substituted aryl,arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, heterocycloalkyl, orsubstituted heterocycloalkyl; and R³ and R⁴ are each independentlyhydrogen or methyl.
 63. A compound according to claim 62, wherein: A is—(C═O)—O—R¹; G is hydroxyl; L is absent; j=3; m=s=1; and R³ and R⁴ arehydrogen.
 64. A compound according to claim 62, wherein: A is—(C═O)—O-tert-butyl; G is hydroxyl; L is absent; j=3; m=s=1; and R³ andR⁴ are hydrogen.
 65. A pharmaceutical composition comprising ananti-hepatitis C virally effective amount of a compound according toclaim 1, 27, 36, 41, 50, 55, or 62, or a pharmaceutically acceptablesalt, ester, or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier or excipient.
 66. A method of treating a hepatitis Cviral infection in a subject, comprising administering to the subject ananti-hepatitis C virally effective amount of a pharmaceuticalcomposition according to claim
 65. 67. A method of inhibiting thereplication of hepatitis C virus, the method comprising supplying ahepatitis C viral NS3 protease inhibitory amount of the pharmaceuticalcomposition of claim
 65. 68. The method of claim 66 further comprisingadministering concurrently an additional anti-hepatitis C virus agent.69. The method of claim 68, wherein said additional anti-hepatitis Cvirus agent is selected from the group consisting of a-interferon,β-interferon, ribavarin, and adamantine.
 70. The method of claim 68,wherein said additional anti-hepatitis C virus agent is an inhibitor ofother targets in the hepatitis C virus life cycle which is selected fromthe group consisting of helicase, polymerase, metal loprotease, andIRES.
 71. A compound selected from the group consisting of:

pharmaceutically, acceptable, salts, and, isomers, thereof,
 72. Acompound selected from the group consisting of:

and pharmaceutically acceptable salts and isomers thereof.
 73. Acompound selected from the group consisting of:

pharmaceutically acceptable salts and isomers thereof.
 74. A method formaking a compound of Formula I in claim 1, comprising the steps of: (i)reacting a proline derivative of formula VI:

wherein, P is a nitrogen-protecting group; L is a leaving group; R isoptionally substituted alkyl, optionally substituted aralkyl, oroptionally substituted heteroaralkyl; with a nucleophilic heterocycliccompound; and (ii) converting the resulting compound to a compound ofFormula I in claim
 1. 75. A method for making a compound of Formula I inclaim 1, comprising the steps of: (i) reacting a compound of formulaVIl:

wherein, L is a leaving group; A is a nitrogen protecting group; and theremaining variables are as defined in claim 1; with a nucleophilicheterocyclic compound; and (ii) converting the resulting compound to acompound of Formula I in claim
 1. 76. The compound of formula I in claim1, wherein W is

wherein V, X, Y, and Z are each independently selected from: j) —C₁-C₆alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; k) —C₂-C₆ alkenylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; l) —C₂-C₆ alkynylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; m) aryl; n)substituted aryl; o) heteroaryl; p) substituted heteroaryl; q)heterocycloalkyl; or r) substituted heterocycloalkyl; or in thealternative, V and X, X and Y, or Y and Z are taken together with thecarbons to which they are attached to for a cyclic moiety selected from:aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl;
 77. The compound offormula I in claim 1, wherein W is

wherein X, Y, and Z are each independently selected from: a) —C₁-C₆alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; b) —C₂-C₆ alkenylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; c) —C₂-C₆ alkynylcontaining 0, 1, 2, or 3 heteroatoms selected from O, S, or N,optionally substituted with one or more substituent selected fromhalogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocycloalkyl, or substituted heterocycloalkyl; d) aryl; e)substituted aryl; f) heteroaryl; g) substituted heteroaryl; h)heterocycloalkyl; or i) substituted heterocycloalkyl; or in thealternative, Y and Z are taken together with the carbons to which theyare attached to for a cyclic moiety selected from: aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, orsubstituted heterocycloalkyl.